86 results on '"Susan Idicula-Thomas"'
Search Results
2. GeDiPNet: Online resource of curated gene-disease associations for polypharmacological targets discovery
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Indra Kundu, Mridula Sharma, Ram Shankar Barai, Khushal Pokar, and Susan Idicula-Thomas
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Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Published
- 2023
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3. Pathway Analysis of Genome Wide Association Studies (GWAS) Data Associated with Male Infertility
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Rupashree Salvi, Ulka Gawde, Susan Idicula-Thomas, and Barnali Biswas
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male infertility ,GWAS ,SNPs ,ICSN ,HLA-DRA ,TNFRSF14 ,Reproduction ,QH471-489 - Abstract
Background: Infertility is a common condition affecting approximately 10–20% of the reproductive age population. Idiopathic infertility cases are thought to have a genetic basis, but the underlying causes are largely unknown. However, the genetic basis underlying male infertility in humans is only partially understood. The Purpose of the study is to understand the current state of research on the genetics of male infertility and its association with significant biological mechanisms. Results: We performed an Identify Candidate Causal SNPs and Pathway (ICSN Pathway) analysis using a genome-wide association study (GWAS) dataset, and NCBI-PubMed search which included 632 SNPs in GWAS and 451 SNPs from the PubMed server, respectively. The ICSN Pathway analysis produced three hypothetical biological mechanisms associated with male infertility: (1) rs8084 and rs7192→HLA-DRA→inflammatory pathways and cell adhesion; rs7550231 and rs2234167→TNFRSF14→TNF Receptor Superfamily Member 14→T lymphocyte proliferation and activation; rs1105879 and rs2070959→UGT1A6→UDP glucuronosyltransferase family 1 member A6→Metabolism of Xenobiotics, androgen, estrogen, retinol, and carbohydrates. Conclusions: We believe that our results may be helpful to study the genetic mechanisms of male infertility. Pathway-based methods have been applied to male infertility GWAS datasets to investigate the biological mechanisms and reported some novel male infertility risk pathways. This pathway analysis using GWAS dataset suggests that the biological process related to inflammation and metabolism might contribute to male infertility susceptibility. Our analysis suggests that genetic contribution to male infertility operates through multiple genes affecting common inflammatory diseases interacting in functional pathways.
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- 2022
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4. Comparison of machine learning algorithms applied to symptoms to determine infectious causes of death in children: national survey of 18,000 verbal autopsies in the Million Death Study in India
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Susan Idicula-Thomas, Ulka Gawde, and Prabhat Jha
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Machine learning ,Prediction model ,Million Death Study ,Verbal autopsy ,Child mortality ,Cause of death ,Public aspects of medicine ,RA1-1270 - Abstract
Abstract Background Machine learning (ML) algorithms have been successfully employed for prediction of outcomes in clinical research. In this study, we have explored the application of ML-based algorithms to predict cause of death (CoD) from verbal autopsy records available through the Million Death Study (MDS). Methods From MDS, 18826 unique childhood deaths at ages 1–59 months during the time period 2004–13 were selected for generating the prediction models of which over 70% of deaths were caused by six infectious diseases (pneumonia, diarrhoeal diseases, malaria, fever of unknown origin, meningitis/encephalitis, and measles). Six popular ML-based algorithms such as support vector machine, gradient boosting modeling, C5.0, artificial neural network, k-nearest neighbor, classification and regression tree were used for building the CoD prediction models. Results SVM algorithm was the best performer with a prediction accuracy of over 0.8. The highest accuracy was found for diarrhoeal diseases (accuracy = 0.97) and the lowest was for meningitis/encephalitis (accuracy = 0.80). The top signs/symptoms for classification of these CoDs were also extracted for each of the diseases. A combination of signs/symptoms presented by the deceased individual can effectively lead to the CoD diagnosis. Conclusions Overall, this study affirms that verbal autopsy tools are efficient in CoD diagnosis and that automated classification parameters captured through ML could be added to verbal autopsies to improve classification of causes of death.
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- 2021
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5. Human surfactant protein D facilitates SARS-CoV-2 pseudotype binding and entry in DC-SIGN expressing cells, and downregulates spike protein induced inflammation
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Nazar Beirag, Chandan Kumar, Taruna Madan, Mohamed H. Shamji, Roberta Bulla, Daniel Mitchell, Valarmathy Murugaiah, Martin Mayora Neto, Nigel Temperton, Susan Idicula-Thomas, Praveen M. Varghese, and Uday Kishore
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innate immune system ,collectins ,rfhSP-D ,SARS-CoV-2 ,COVID-19 ,cytokine response ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Lung surfactant protein D (SP-D) and Dendritic cell-specific intercellular adhesion molecules-3 grabbing non-integrin (DC-SIGN) are pathogen recognising C-type lectin receptors. SP-D has a crucial immune function in detecting and clearing pulmonary pathogens; DC-SIGN is involved in facilitating dendritic cell interaction with naïve T cells to mount an anti-viral immune response. SP-D and DC-SIGN have been shown to interact with various viruses, including SARS-CoV-2, an enveloped RNA virus that causes COVID-19. A recombinant fragment of human SP-D (rfhSP-D) comprising of α-helical neck region, carbohydrate recognition domain, and eight N-terminal Gly-X-Y repeats has been shown to bind SARS-CoV-2 Spike protein and inhibit SARS-CoV-2 replication by preventing viral entry in Vero cells and HEK293T cells expressing ACE2. DC-SIGN has also been shown to act as a cell surface receptor for SARS-CoV-2 independent of ACE2. Since rfhSP-D is known to interact with SARS-CoV-2 Spike protein and DC-SIGN, this study was aimed at investigating the potential of rfhSP-D in modulating SARS-CoV-2 infection. Coincubation of rfhSP-D with Spike protein improved the Spike Protein: DC-SIGN interaction. Molecular dynamic studies revealed that rfhSP-D stabilised the interaction between DC-SIGN and Spike protein. Cell binding analysis with DC-SIGN expressing HEK 293T and THP- 1 cells and rfhSP-D treated SARS-CoV-2 Spike pseudotypes confirmed the increased binding. Furthermore, infection assays using the pseudotypes revealed their increased uptake by DC-SIGN expressing cells. The immunomodulatory effect of rfhSP-D on the DC-SIGN: Spike protein interaction on DC-SIGN expressing epithelial and macrophage-like cell lines was also assessed by measuring the mRNA expression of cytokines and chemokines. RT-qPCR analysis showed that rfhSP-D treatment downregulated the mRNA expression levels of pro-inflammatory cytokines and chemokines such as TNF-α, IFN-α, IL-1β, IL- 6, IL-8, and RANTES (as well as NF-κB) in DC-SIGN expressing cells challenged by Spike protein. Furthermore, rfhSP-D treatment was found to downregulate the mRNA levels of MHC class II in DC expressing THP-1 when compared to the untreated controls. We conclude that rfhSP-D helps stabilise the interaction between SARS- CoV-2 Spike protein and DC-SIGN and increases viral uptake by macrophages via DC-SIGN, suggesting an additional role for rfhSP-D in SARS-CoV-2 infection.
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- 2022
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6. Enrichment analyses of diseases and pathways associated with precocious puberty using PrecocityDB
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Mridula Sharma, Indra Kundu, Ram Shankar Barai, Sameeksha Bhaye, Karishma Desai, Khushal Pokar, and Susan Idicula-Thomas
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Medicine ,Science - Abstract
Abstract Precocious puberty (PP) is an important endocrine disorder affecting children globally. Several genes, SNPs and comorbidities are reported to be associated with PP; however, this data is scattered across scientific literature and has not been systematically collated and analysed. In this study, we present PrecocityDB as the first manually curated online database on genes and their ontology terms, SNPs, and pathways associated with PP. A tool for visualizing SNP coordinates and allelic variation on each chromosome, for genes associated with PP is also incorporated in PrecocityDB. Pathway enrichment analysis of PP-associated genes revealed that endocrine and cancer-related pathways are highly enriched. Disease enrichment analysis indicated that individuals with PP seem to be highly likely to suffer from reproductive and metabolic disorders such as PCOS, hypogonadism, and insulin resistance. PrecocityDB is a useful resource for identification of comorbid conditions and disease risks due to shared genes in PP. PrecocityDB is freely accessible at http://www.precocity.bicnirrh.res.in . The database source code and content can be downloaded through GitHub ( https://github.com/bic-nirrh/precocity ).
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- 2021
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7. Meta-analysis of gene expression profiles of lean and obese PCOS to identify differentially regulated pathways and risk of comorbidities
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Susan Idicula-Thomas, Ulka Gawde, Sameeksha Bhaye, Khushal Pokar, and Gary D. Bader
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PCOS ,Differential gene expression ,Pathway analysis ,Enrichment analysis ,Comorbidity analysis ,Biotechnology ,TP248.13-248.65 - Abstract
Polycystic ovary syndrome (PCOS) is a complex multigenic disorder and women with PCOS suffer from several comorbidities. Although, obesity is a known risk factor for PCOS, the incidence of lean women with PCOS is on the rise. A systematic and comparative study on lean and obese PCOS with respect to genes, pathways and comorbidity analysis has not been attempted so far. Analysis of differentially expressed genes (DEGs) across tissue types for lean and obese PCOS revealed that the majority of them were downregulated for lean and obese PCOS. Ovarian and endometrial tissues shared several commonly dysregulated genes, suggesting shared PCOS pathophysiology mechanisms exist across tissues. Several pathways for cellular homeostasis, such as inflammation and immune response, insulin signaling, steroidogenesis, hormonal and metabolic signaling, regulation of gonadotrophic hormone secretion, cell structure and signaling that are known to be affected in PCOS were found to be enriched in our gene expression analysis of lean and obese PCOS. The gene-disease network is denser for obese PCOS with a higher comorbidity score as compared to lean PCOS.
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- 2020
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8. Human Properdin Released By Infiltrating Neutrophils Can Modulate Influenza A Virus Infection
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Praveen M. Varghese, Shuvechha Mukherjee, Futwan A. Al-Mohanna, Souad M. Saleh, Fahad N. Almajhdi, Nazar Beirag, Saad H. Alkahtani, Reena Rajkumari, Beatrice Nal Rogier, Robert B. Sim, Susan Idicula-Thomas, Taruna Madan, Valarmathy Murugaiah, and Uday Kishore
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innate immune system ,complement system ,complement evasion ,human properdin ,RNA viruses ,influenza A virus ,Immunologic diseases. Allergy ,RC581-607 - Abstract
The complement system is designed to recognise and eliminate invading pathogens via activation of classical, alternative and lectin pathways. Human properdin stabilises the alternative pathway C3 convertase, resulting in an amplification loop that leads to the formation of C5 convertase, thereby acting as a positive regulator of the alternative pathway. It has been noted that human properdin on its own can operate as a pattern recognition receptor and exert immune functions outside its involvement in complement activation. Properdin can bind directly to microbial targets via DNA, sulfatides and glycosaminoglycans, apoptotic cells, nanoparticles, and well-known viral virulence factors. This study was aimed at investigating the complement-independent role of properdin against Influenza A virus infection. As one of the first immune cells to arrive at the site of IAV infection, we show here that IAV challenged neutrophils released properdin in a time-dependent manner. Properdin was found to directly interact with haemagglutinin, neuraminidase and matrix 1 protein Influenza A virus proteins in ELISA and western blot. Furthermore, modelling studies revealed that properdin could bind HA and NA of the H1N1 subtype with higher affinity compared to that of H3N2 due to the presence of an HA cleavage site in H1N1. In an infection assay using A549 cells, properdin suppressed viral replication in pH1N1 subtype while promoting replication of H3N2 subtype, as revealed by qPCR analysis of M1 transcripts. Properdin treatment triggered an anti-inflammatory response in H1N1-challenged A549 cells and a pro-inflammatory response in H3N2-infected cells, as evident from differential mRNA expression of TNF-α, NF-κB, IFN-α, IFN-β, IL-6, IL-12 and RANTES. Properdin treatment also reduced luciferase reporter activity in MDCK cells transduced with H1N1 pseudotyped lentiviral particles; however, it was increased in the case of pseudotyped H3N2 particles. Collectively, we conclude that infiltrating neutrophils at the site of IAV infection can release properdin, which then acts as an entry inhibitor for pandemic H1N1 subtype while suppressing viral replication and inducing an anti-inflammatory response. H3N2 subtype can escape this immune restriction due to altered haemagglutinin and neuraminindase, leading to enhanced viral entry, replication and pro-inflammatory response. Thus, depending on the subtype, properdin can either limit or aggravate IAV infection in the host.
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- 2021
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9. N-Linked Glycosylation in Chinese Hamster Ovary Cells Is Critical for Insulin-like Growth Factor 1 Signaling
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Rupashree Salvi, Chandan Kumar, Krupanshi Brahmbhatt, Rambhadur Subedi, Susan Idicula-Thomas, Taruna Madan, and Barnali Biswas
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N-glycosylation ,Orbitrap Mass Spectrometry (MS) ,insulin-like growth factor 1 receptor ,Ras GTPase activating Protein (IQGAP1) ,integrins ,receptor tyrosine kinase ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Cell surface proteins carrying N-glycans play important roles in inter- and intracellular processes including cell adhesion, development, and cellular recognition. Dysregulation of the glycosylation machinery has been implicated in various diseases, and investigation of global differential cell surface proteome effects due to the loss of N-glycosylation will provide comprehensive insights into their pathogenesis. Cell surface proteins isolated from Parent Pro–5 CHO cells (W5 cells), two CHO mutants with loss of N-glycosylation function derived from Pro–5 CHO (Lec1 and Lec4 cells), were subjected to proteome analysis via high-resolution LCMS. We identified 44 and 43 differentially expressed membrane proteins in Lec1 and Lec4 cells, respectively, as compared to W5 cells. The defective N-glycosylation mutants showed increased abundance of integrin subunits in Lec1 and Lec4 cells at the cell surface. We also found significantly reduced levels of IGF-1R (Insulin like growth factor-1 receptor); a receptor tyrosine kinase; and the GTPase activating protein IQGAP1 (IQ motif-containing GTPase activating protein), a highly conserved cytoplasmic scaffold protein) in Lec1 and Lec4 cells. In silico docking studies showed that the IQ domain of IQGAP1 interacts with the kinase domain of IGF-1R. The integrin signaling and insulin growth factor receptor signaling were also enriched according to GSEA analysis and pathway analysis of differentially expressed proteins. Significant reductions of phosphorylation of ERK1 and ERK2 in Lec1 and Lec4 cells were observed upon IGF-1R ligand (IGF-1 LR3) stimulation. IGF-1 LR3, known as Long arginine3-IGF-1, is a synthetic protein and lengthened analog of insulin-like growth factor 1. The work suggests a novel mechanism for the activation of IGF-1 dependent ERK signaling in CHO cells, wherein IQGAP1 plausibly functions as an IGF-1R-associated scaffold protein. Appropriate glycosylation by the enzymes MGAT1 and MGAT5 is thus essential for processing of cell surface receptor IGF-1R, a potential binding partner in IQGAP1 and ERK signaling, the integral components of the IGF pathway.
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- 2022
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10. Membrane Interactome of a Recombinant Fragment of Human Surfactant Protein D Reveals GRP78 as a Novel Binding Partner in PC3, a Metastatic Prostate Cancer Cell Line
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Gargi Thakur, Gajanan Sathe, Indra Kundu, Barnali Biswas, Poonam Gautam, Saad Alkahtani, Susan Idicula-Thomas, Ravi Sirdeshmukh, Uday Kishore, and Taruna Madan
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surfactant protein D ,GRP78 ,interactome analysis ,prostate cancer ,apoptosis ,signaling ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Surfactant protein-D (SP-D), a member of the collectin family has been shown to induce apoptosis in cancer cells. SP-D is composed of an N-terminal collagen-like domain and a calcium-dependent carbohydrate recognition domain (CRD). Recently, we reported that a recombinant fragment of human SP-D (rfhSP-D), composed of homotrimeric CRD region, induced intrinsic apoptotic pathway in prostate cancer cells. Here, we analyzed the membrane interactome of rfhSP-D in an androgen-independent prostate cancer cell line, PC3, by high resolution mass spectrometry and identified 347 proteins. Computational analysis of PPI network of this interactome in the context of prostate cancer metastasis and apoptosis revealed Glucose Regulated Protein of 78 kDa (GRP78) as an important binding partner of rfhSP-D. Docking studies suggested that rfhSP-D (CRD) bound to the substrate-binding domain of glycosylated GRP78. This was further supported by the observations that human recombinant GRP78 interfered with the binding of rfhSP-D to anti-SP-D polyclonal antibodies; GRP78 also significantly inhibited the binding of recombinant full-length human SP-D with a monoclonal antibody specific to the CRD in a dose-dependent manner. We conclude that the interaction with rfhSP-D is likely to interfere with the pro-survival signaling of GRP78.
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- 2021
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11. Designing Antibacterial Peptides with Enhanced Killing Kinetics
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Faiza H. Waghu, Shaini Joseph, Sanket Ghawali, Elvis A. Martis, Taruna Madan, Kareenhalli V. Venkatesh, and Susan Idicula-Thomas
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antibacterial peptides ,MD simulation ,killing kinetics ,microbial membrane ,rational design ,Microbiology ,QR1-502 - Abstract
Antimicrobial peptides (AMPs) are gaining attention as substitutes for antibiotics in order to combat the risk posed by multi-drug resistant pathogens. Several research groups are engaged in design of potent anti-infective agents using natural AMPs as templates. In this study, a library of peptides with high sequence similarity to Myeloid Antimicrobial Peptide (MAP) family were screened using popular online prediction algorithms. These peptide variants were designed in a manner to retain the conserved residues within the MAP family. The prediction algorithms were found to effectively classify peptides based on their antimicrobial nature. In order to improve the activity of the identified peptides, molecular dynamics (MD) simulations, using bilayer and micellar systems could be used to design and predict effect of residue substitution on membranes of microbial and mammalian cells. The inference from MD simulation studies well corroborated with the wet-lab observations indicating that MD-guided rational design could lead to discovery of potent AMPs. The effect of the residue substitution on membrane activity was studied in greater detail using killing kinetic analysis. Killing kinetics studies on Gram-positive, negative and human erythrocytes indicated that a single residue change has a drastic effect on the potency of AMPs. An interesting outcome was a switch from monophasic to biphasic death rate constant of Staphylococcus aureus due to a single residue mutation in the peptide.
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- 2018
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12. Protein–Protein Interaction between Surfactant Protein D and DC-SIGN via C-Type Lectin Domain Can Suppress HIV-1 Transfer
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Eswari Dodagatta-Marri, Daniel A. Mitchell, Hrishikesh Pandit, Archana Sonawani, Valarmathy Murugaiah, Susan Idicula-Thomas, Béatrice Nal, Maha M. Al-Mozaini, Anuvinder Kaur, Taruna Madan, and Uday Kishore
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surfactant protein D ,DC-SIGN ,HIV-1 infection ,protein–protein interactions ,gp120 ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Surfactant protein D (SP-D) is a soluble C-type lectin, belonging to the collectin (collagen-containing calcium-dependent lectin) family, which acts as an innate immune pattern recognition molecule in the lungs at other mucosal surfaces. Immune regulation and surfactant homeostasis are salient functions of SP-D. SP-D can bind to a range of viral, bacterial, and fungal pathogens and trigger clearance mechanisms. SP-D binds to gp120, the envelope protein expressed on HIV-1, through its C-type lectin or carbohydrate recognition domain. This is of importance since SP-D is secreted by human mucosal epithelial cells and is present in the female reproductive tract, including vagina. Another C-type lectin, dendritic cell (DC)-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), present on the surface of the DCs, also binds to HIV-1 gp120 and facilitates viral transfer to the lymphoid tissues. DCs are also present at the site of HIV-1 entry, embedded in vaginal or rectal mucosa. In the present study, we report a direct protein–protein interaction between recombinant forms of SP-D (rfhSP-D) and DC-SIGN via their C-type lectin domains. Both SP-D and DC-SIGN competed for binding to immobilized HIV-1 gp120. Pre-incubation of human embryonic kidney cells expressing surface DC-SIGN with rfhSP-D significantly inhibited the HIV-1 transfer to activated peripheral blood mononuclear cells. In silico analysis revealed that SP-D and gp120 may occupy same sites on DC-SIGN, which may explain the reduced transfer of HIV-1. In summary, we demonstrate, for the first time, that DC-SIGN is a novel binding partner of SP-D, and this interaction can modulate HIV-1 capture and transfer to CD4+ T cells. In addition, the present study also reveals a novel and distinct mechanism of host defense by SP-D against HIV-1.
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- 2017
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13. Surfactant protein D inhibits HIV-1 infection of target cells via interference with gp120-CD4 interaction and modulates pro-inflammatory cytokine production.
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Hrishikesh Pandit, Sandhya Gopal, Archana Sonawani, Ajit Kumar Yadav, Asif S Qaseem, Himangi Warke, Anushree Patil, Rahul Gajbhiye, Vijay Kulkarni, Maha Ahmed Al-Mozaini, Susan Idicula-Thomas, Uday Kishore, and Taruna Madan
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Medicine ,Science - Abstract
Surfactant Protein SP-D, a member of the collectin family, is a pattern recognition protein, secreted by mucosal epithelial cells and has an important role in innate immunity against various pathogens. In this study, we confirm that native human SP-D and a recombinant fragment of human SP-D (rhSP-D) bind to gp120 of HIV-1 and significantly inhibit viral replication in vitro in a calcium and dose-dependent manner. We show, for the first time, that SP-D and rhSP-D act as potent inhibitors of HIV-1 entry in to target cells and block the interaction between CD4 and gp120 in a dose-dependent manner. The rhSP-D-mediated inhibition of viral replication was examined using three clinical isolates of HIV-1 and three target cells: Jurkat T cells, U937 monocytic cells and PBMCs. HIV-1 induced cytokine storm in the three target cells was significantly suppressed by rhSP-D. Phosphorylation of key kinases p38, Erk1/2 and AKT, which contribute to HIV-1 induced immune activation, was significantly reduced in vitro in the presence of rhSP-D. Notably, anti-HIV-1 activity of rhSP-D was retained in the presence of biological fluids such as cervico-vaginal lavage and seminal plasma. Our study illustrates the multi-faceted role of human SP-D against HIV-1 and potential of rhSP-D for immunotherapy to inhibit viral entry and immune activation in acute HIV infection.
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- 2014
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14. In silico study on binding specificity of gonadotropins and their receptors: design of a novel and selective peptidomimetic for human follicle stimulating hormone receptor.
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Archana Sonawani, Sarfaraj Niazi, and Susan Idicula-Thomas
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Medicine ,Science - Abstract
Gonadotropins bind to specific receptors in spite of sharing a high level of sequence and structural similarity. This specific binding is crucial for maintaining the reproductive health of an organism. In this study, residues that dictate the receptor binding specificity of the gonadotropins (FSH and LH) have been identified using combination of in silico methods. Docking studies (ZDOCK), based on the systematic replacement of these residues, confirmed its importance in receptor binding. An interesting observation is that the relative positioning of the residues conferring binding specificity varied for the gonadotropin-receptor complexes. This spatial difference of the key residues could be exploited for design of specific modulators. Based on the identified residues, we have rationally designed a peptidomimetic (FSHP) that displays good binding affinity and specificity for hFSHR. FSHP was developed by screening 3.9 million compounds using pharmacophore-shape similarity followed by fragment-based approach. It was observed that FSHP and hFSHâ can share the same receptor binding site thereby mimicking the native hFSHR-FSH interactions. FSHP also displayed higher binding affinity to hFSHR as compared to two reported hFSHR antagonists. MD simulation studies on hFSHR-FSHP complex revealed that FSHP is conformationally rigid and the intermolecular interactions are maintained during the course of simulation.
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- 2013
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15. Correction: In Silico Study on Binding Specificity of Gonadotropins and Their Receptors: Design of a Novel and Selective Peptidomimetic for Human Follicle Stimulating Hormone Receptor.
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Archana Sonawani, Sarfaraj Niazi, and Susan Idicula-Thomas
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Medicine ,Science - Abstract
[This corrects the article DOI: 10.1371/journal.pone.0064475.].
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- 2013
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16. Identification of novel mutations in HEXA gene in children affected with Tay Sachs disease from India.
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Mehul Mistri, Parag M Tamhankar, Frenny Sheth, Daksha Sanghavi, Pratima Kondurkar, Swapnil Patil, Susan Idicula-Thomas, Sarita Gupta, and Jayesh Sheth
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Medicine ,Science - Abstract
Tay Sachs disease (TSD) is a neurodegenerative disorder due to β-hexosaminidase A deficiency caused by mutations in the HEXA gene. The mutations leading to Tay Sachs disease in India are yet unknown. We aimed to determine mutations leading to TSD in India by complete sequencing of the HEXA gene. The clinical inclusion criteria included neuroregression, seizures, exaggerated startle reflex, macrocephaly, cherry red spot on fundus examination and spasticity. Neuroimaging criteria included thalamic hyperdensities on CT scan/T1W images of MRI of the brain. Biochemical criteria included deficiency of hexosaminidase A (less than 2% of total hexosaminidase activity for infantile patients). Total leukocyte hexosaminidase activity was assayed by 4-methylumbelliferyl-N-acetyl-β-D-glucosamine lysis and hexosaminidase A activity was assayed by heat inactivation method and 4-methylumbelliferyl-N-acetyl-β-D-glucosamine-6-sulphate lysis method. The exons and exon-intron boundaries of the HEXA gene were bidirectionally sequenced using an automated sequencer. Mutations were confirmed in parents and looked up in public databases. In silico analysis for mutations was carried out using SIFT, Polyphen2, MutationT@ster and Accelrys Discovery Studio softwares. Fifteen families were included in the study. We identified six novel missense mutations, c.340 G>A (p.E114K), c.964 G>A (p.D322N), c.964 G>T (p.D322Y), c.1178C>G (p.R393P) and c.1385A>T (p.E462V), c.1432 G>A (p.G478R) and two previously reported mutations. c.1277_1278insTATC and c.508C>T (p.R170W). The mutation p.E462V was found in six unrelated families from Gujarat indicating a founder effect. A previously known splice site mutation c.805+1 G>C and another intronic mutation c.672+30 T>G of unknown significance were also identified. Mutations could not be identified in one family. We conclude that TSD patients from Gujarat should be screened for the common mutation p.E462V.
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- 2012
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17. CAMPR4: a database of natural and synthetic antimicrobial peptides.
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Ulka Gawde, Shuvechha Chakraborty, Faiza Hanif Waghu, Ram Shankar Barai, Ashlesha Khanderkar, Rishikesh Indraguru, Tanmay Shirsat, and Susan Idicula-Thomas
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- 2023
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18. FSHR activation through small molecule modulators: Mechanistic insights from MD simulations.
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Chandan Kumar and Susan Idicula-Thomas
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- 2023
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19. Expanding the therapeutic options for Candida infections using novel inhibitors of secreted aspartyl proteases
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Shuvechha Chakraborty, Kshitija Rahate, Chandan Kumar, and Susan Idicula‐Thomas
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Drug Discovery - Abstract
For widening the therapeutic options for Candida management, the druggability of Candida proteome was systematically investigated using an innovative pipeline of high-throughput data mining algorithms, followed by in vitro validation of the observations. Through this exercise, HIV-1 protease was found to share structural similarity with secreted aspartyl protease-3 (SAP3), a virulence protein of Candida. Using the molecular fingerprint of HIV-1 protease inhibitor GRL-09510, we performed virtual screening of peptidomimetic library followed by high-precision docking and MD simulations for discovery of SAP inhibitors. Wet-lab validation of the four shortlisted peptidomimetics revealed that two molecules, when used in combination with fluconazole, could significantly reduce the dosage of fluconazole required for 50% inhibition of Candida albicans. The SAP inhibitory activity of these peptidomimetics was confirmed through SAP assays and found to be on par with pepstatin A, a known peptidomimetic inhibitor of aspartyl proteases.
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- 2022
20. CAMPR4: a database of natural and synthetic antimicrobial peptides
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Ulka Gawde, Shuvechha Chakraborty, Faiza Hanif Waghu, Ram Shankar Barai, Ashlesha Khanderkar, Rishikesh Indraguru, Tanmay Shirsat, and Susan Idicula-Thomas
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Genetics - Abstract
There has been an exponential increase in the design of synthetic antimicrobial peptides (AMPs) for its use as novel antibiotics. Synthetic AMPs are substantially enriched in residues with physicochemical properties known to be critical for antimicrobial activity; such as positive charge, hydrophobicity, and higher alpha helical propensity. The current prediction algorithms for AMPs have been developed using AMP sequences from natural sources and hence do not perform well for synthetic peptides. In this version of CAMP database, along with updating sequence information of AMPs, we have created separate prediction algorithms for natural and synthetic AMPs. CAMPR4 holds 24243 AMP sequences, 933 structures, 2143 patents and 263 AMP family signatures. In addition to the data on sequences, source organisms, target organisms, minimum inhibitory and hemolytic concentrations, CAMPR4 provides information on N and C terminal modifications and presence of unusual amino acids, as applicable. The database is integrated with tools for AMP prediction and rational design (natural and synthetic AMPs), sequence (BLAST and clustal omega), structure (VAST) and family analysis (PRATT, ScanProsite, CAMPSign). The data along with the algorithms of CAMPR4 will aid to enhance AMP research. CAMPR4 is accessible at http://camp.bicnirrh.res.in/.
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- 2022
21. PCOSKB: A KnowledgeBase on genes, diseases, ontology terms and biochemical pathways associated with PolyCystic Ovary Syndrome.
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Shaini Joseph, Ram Shankar Barai, Rasika Bhujbalrao, and Susan Idicula-Thomas
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- 2016
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22. CAMPR3: a database on sequences, structures and signatures of antimicrobial peptides.
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Faiza Hanif Waghu, Ram Shankar Barai, Pratima Gurung, and Susan Idicula-Thomas
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- 2016
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23. PBIT: Pipeline Builder for Identification of drug Targets for infectious diseases.
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Gauri Shende, Harshala Haldankar, Ram Shankar Barai, Mohammed Husain Bharmal, Vinit Shetty, and Susan Idicula-Thomas
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- 2017
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24. A Recombinant Fragment of Human Surfactant Protein D Binds Spike Protein and Inhibits Infectivity and Replication of SARS-CoV-2 in Clinical Samples
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Uday Kishore, Ekta Gupta, Hrishikesh Pandit, Indra Kundu, Sheetalnath Rooge, Savneet Kaur, Reshu Agarwal, Sanjeev Gupta, Taruna Madan, Dinesh M. Tripathi, Susan Idicula-Thomas, Praveen M. Varghese, Rambhadur Subedi, and Barnali Biswas
- Subjects
entry inhibition ,Male ,0301 basic medicine ,viruses ,Clinical Biochemistry ,Plasma protein binding ,Virus Replication ,spike protein ,medicine.disease_cause ,law.invention ,0302 clinical medicine ,law ,Chlorocebus aethiops ,Receptor ,skin and connective tissue diseases ,Pulmonary Surfactant-Associated Protein D ,Original Research ,Coronavirus ,Infectivity ,Chemistry ,virus diseases ,Recombinant Proteins ,Spike Glycoprotein, Coronavirus ,Recombinant DNA ,Female ,Protein Binding ,medicine.drug ,Adult ,Pulmonary and Respiratory Medicine ,surfactant protein D ,Protein subunit ,Virus ,03 medical and health sciences ,medicine ,Animals ,Humans ,Gene ,Vero Cells ,Molecular Biology ,entry inhibitor ,SARS-CoV-2 ,fungi ,COVID-19 ,Surfactant protein D ,Cell Biology ,Molecular biology ,Virology ,Entry inhibitor ,body regions ,030104 developmental biology ,030228 respiratory system ,Viral replication - Abstract
RationaleCOVID-19 is an acute infectious disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Human surfactant protein D (SP-D) is known to interact with spike protein of SARS-CoV, but its immune-surveillance against SARS-CoV-2 is not known.ObjectiveThis study aimed to examine the potential of a recombinant fragment of human SP-D (rfhSP-D) as an inhibitor of replication and infection of SARS-CoV-2.MethodsrfhSP-D interaction with spike protein of SARS-CoV-2 and hACE-2 receptor was predicted via docking analysis. The inhibition of interaction between spike protein and ACE-2 by rfhSP-D was confirmed using direct and indirect ELISA. The effect of rfhSP-D on replication and infectivity of SARS-CoV-2 from clinical samples was studied by measuring the expression of RdRp gene of the virus using qPCR.Measurements and Main ResultsIn-silico interaction studies indicated that three amino acid residues in the RBD of spike of SARS-CoV-2 were commonly involved in interacting with rfhSP-D and ACE-2. Studies using clinical samples of SARS-CoV-2 positive cases (asymptomatic, n=7 and symptomatic, n=8 and negative controls n=15) demonstrated that treatment with 5μM rfhSP-D inhibited viral replication by ~5.5 fold and was more efficient than Remdesivir (100 μM). Approximately, a 2-fold reduction in viral infectivity was also observed after treatment with 5μM rfhSP-D.ConclusionsThese results conclusively demonstrate that the calcium independent rfhSP-D mediated inhibition of binding between the receptor binding domain of the S1 subunit of the SARS-CoV-2 spike protein and human ACE-2, its host cell receptor, and a significant reduction in SARS-CoV-2 infection and replication in-vitro.
- Published
- 2021
25. CAMP: Collection of sequences and structures of antimicrobial peptides.
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Faiza Hanif Waghu, Lijin Gopi, Ram Shankar Barai, Pranay Ramteke, Bilal Nizami, and Susan Idicula-Thomas
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- 2014
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26. Exploring the druggable proteome of Candida species through comprehensive computational analysis
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Shuvechha Mukherjee, Susan Idicula-Thomas, Mehdi Askari, Indra Kundu, Ram Shankar Barai, and Kareenhalli V. Venkatesh
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0106 biological sciences ,Antifungal Agents ,Proteome ,In silico ,Systems biology ,Druggability ,Genomics ,Computational biology ,Secondary metabolite ,01 natural sciences ,Fungal Proteins ,Candida tropicalis ,03 medical and health sciences ,Candida albicans ,Drug Discovery ,Genetics ,medicine ,030304 developmental biology ,0303 health sciences ,biology ,Drug Repositioning ,Computational Biology ,Bridged Bicyclo Compounds, Heterocyclic ,biology.organism_classification ,Metabolic Flux Analysis ,Diterpenes ,Software ,Protein Binding ,010606 plant biology & botany ,medicine.drug - Abstract
Candida albicans and non-albicans Candida spp. are major cause of systemic mycoses. Antifungal drugs such as azoles and polyenes are not efficient to successfully eradicate Candida infection owing to their fungistatic nature or low bioavailability. Here, we have adopted a comprehensive computational workflow for identification, prioritization and validation of targets from proteomes of Candida albicans and Candida tropicalis. The protocol involves identification of essential drug-target candidates using subtractive genomics, protein-protein interaction network properties and systems biology based methods. The essentiality of the novel metabolic and non-metabolic targets was established by performing in silico gene knockouts, under aerobic as well as anaerobic conditions, and in vitro drug inhibition assays respectively. Deletion of twelve genes that are involved in amino acid, secondary metabolite, and carbon metabolism showed zero growth in metabolic model under simulated conditions. The algorithm, used in this study, can be downloaded from http://pbit.bicnirrh.res.in/offline.php and executed locally.
- Published
- 2021
27. Multimorbidity landscape of schizophrenia: Insights from meta-analysis of genome wide association studies
- Author
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Ulka Gawde, Priyanka Hegde, Karishma Desai, Ram Shankar Barai, Bipin Raj Shekhar, Dhanjit K. Das, and Susan Idicula-Thomas
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Psychiatry and Mental health ,Schizophrenia ,Humans ,Multimorbidity ,Genetic Predisposition to Disease ,Polymorphism, Single Nucleotide ,Biological Psychiatry ,Genome-Wide Association Study - Published
- 2022
28. ClassAMP: A Prediction Tool for Classification of Antimicrobial Peptides.
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Shaini Joseph, Shreyas Karnik, Pravin Nilawe, Vaidyanathan K. Jayaraman, and Susan Idicula-Thomas
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- 2012
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29. CAMP: a useful resource for research on antimicrobial peptides.
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Shaini Thomas, Shreyas Karnik, Ram Shankar Barai, Vaidyanathan K. Jayaraman, and Susan Idicula-Thomas
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- 2010
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30. Meta-analysis of gene expression profiles of lean and obese PCOS to identify differentially regulated pathways and risk of comorbidities
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Khushal Pokar, Susan Idicula-Thomas, Ulka Gawde, Gary D. Bader, and Sameeksha Bhaye
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medicine.medical_specialty ,endocrine system diseases ,Pathway analysis ,lcsh:Biotechnology ,Biophysics ,Cellular homeostasis ,Inflammation ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Structural Biology ,lcsh:TP248.13-248.65 ,Internal medicine ,Genetics ,medicine ,PCOS ,GEO, Gene Expression Omnibus ,Risk factor ,Differential gene expression ,030304 developmental biology ,ComputingMethodologies_COMPUTERGRAPHICS ,0303 health sciences ,Enrichment analysis ,biology ,business.industry ,PCOS, Polycystic ovary syndrome ,nutritional and metabolic diseases ,medicine.disease ,Comorbidity ,Polycystic ovary ,Obesity ,female genital diseases and pregnancy complications ,Computer Science Applications ,Insulin receptor ,Endocrinology ,030220 oncology & carcinogenesis ,biology.protein ,Comorbidity analysis ,medicine.symptom ,DEGs, Differentially expressed genes ,business ,Biotechnology ,Hormone ,Research Article - Abstract
Graphical abstract, Polycystic ovary syndrome (PCOS) is a complex multigenic disorder and women with PCOS suffer from several comorbidities. Although, obesity is a known risk factor for PCOS, the incidence of lean women with PCOS is on the rise. A systematic and comparative study on lean and obese PCOS with respect to genes, pathways and comorbidity analysis has not been attempted so far. Analysis of differentially expressed genes (DEGs) across tissue types for lean and obese PCOS revealed that the majority of them were downregulated for lean and obese PCOS. Ovarian and endometrial tissues shared several commonly dysregulated genes, suggesting shared PCOS pathophysiology mechanisms exist across tissues. Several pathways for cellular homeostasis, such as inflammation and immune response, insulin signaling, steroidogenesis, hormonal and metabolic signaling, regulation of gonadotrophic hormone secretion, cell structure and signaling that are known to be affected in PCOS were found to be enriched in our gene expression analysis of lean and obese PCOS. The gene-disease network is denser for obese PCOS with a higher comorbidity score as compared to lean PCOS.
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- 2020
31. Correlation Between the Structural Stability and Aggregation Propensity of Proteins.
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Susan Idicula-Thomas and Petety V. Balaji
- Published
- 2007
32. A support vector machine-based method for predicting the propensity of a protein to be soluble or to form inclusion body on overexpression in Escherichia coli.
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Susan Idicula-Thomas, Abhijit J. Kulkarni, Bhaskar D. Kulkarni, Valadi K. Jayaraman, and Petety V. Balaji
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- 2006
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33. Mapping of FSHR agonists and antagonists binding sites to identify potential peptidomimetic modulators
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Muthu Sankar Aathi, Chandan Kumar, Kaushiki S. Prabhudesai, Dhivya Shanmugarajan, and Susan Idicula-Thomas
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Binding Sites ,Databases, Factual ,Biophysics ,Cell Biology ,Molecular Dynamics Simulation ,Biochemistry ,Molecular Docking Simulation ,HEK293 Cells ,Allosteric Regulation ,Protein Domains ,Peptide Library ,Humans ,Receptors, FSH ,Peptidomimetics - Abstract
Owing to the critical role of follicle stimulating hormone receptor (FSHR) signaling in human reproduction, FSHR has been widely explored for development of fertility regulators. Using high-throughput screening approaches, several low molecular weight (LMW) compounds that can modulate FSHR activity have been identified. However, the information about the binding sites of these molecules on FSHR is not known. In the present study, we extracted the structural and functional information of 161 experimentally validated LMW FSHR modulators available in PubMed records. The potential FSHR binding sites for these modulators were identified through molecular docking experiments. The binding sites were further mapped to the agonist or antagonist activity reported for these molecules in literature. MD simulations were performed to evaluate the effect of ligand binding on conformational changes in the receptor, specifically the transmembrane domain. A peptidomimetic library was screened using these binding sites. Six peptidomimetics that interacted with the residues of transmembrane domain and extracellular loops were evaluated for binding activity using in vitro cAMP assay. Two of the six peptidomimetics exhibited positive allosteric modulatory activity and four peptidomimetics exhibited negative allosteric modulatory activity. All six peptidomimetics interacted with Asp521 of hFSHR(TMD). Several of the experimentally known LMW FSHR modulators also participated in H-bond interactions with Asp521, suggesting its important role in FSHR modulatory activity.
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- 2021
34. Collection of antimicrobial peptides database and its derivatives: Applications and beyond
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Faiza Hanif Waghu and Susan Idicula-Thomas
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Antifungal ,0303 health sciences ,Tools for Protein Science ,Structure analysis ,medicine.drug_class ,Computer science ,030302 biochemistry & molecular biology ,Antimicrobial peptides ,Computational Biology ,Molecular Sequence Annotation ,Computational biology ,Cloud Computing ,Biochemistry ,Markov Chains ,Anti-Bacterial Agents ,Machine Learning ,03 medical and health sciences ,Identification (information) ,medicine ,Amino Acid Sequence ,Databases, Protein ,Peptides ,Hidden Markov model ,Molecular Biology ,030304 developmental biology - Abstract
Collection of antimicrobial peptides (CAMP), CAMPSign, and ClassAMP are open‐access resources that have been developed to enhance research on antimicrobial peptides (AMPs). Comprehensive information on AMPs and machine learning‐based predictive models are made available for users through these resources. As of date, CAMP(R3) has 10,247 sequences, 757 structures, and 114 family‐specific signatures of AMPs along with associated tools for AMP sequence and structure analysis. CAMPSign uses family‐specific sequence conservation, in the form of patterns and hidden Markov models for identification of AMPs. ClassAMP can be used to classify AMPs as antibacterial, antifungal, or antiviral based on sequence information. Here we describe CAMP and its derivatives and illustrate, with a few examples, the contribution of these online resources to the advancement of our current understanding of AMPs.
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- 2019
35. Discovery of small molecule binders of human FSHR(TMD) with novel structural scaffolds by integrating structural bioinformatics and machine learning algorithms
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Sanchi Shah, Bhawana Sahu, Susan Idicula-Thomas, Kaushiki S. Prabhudesai, and Alessandro Contini
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Models, Molecular ,0301 basic medicine ,endocrine system ,Quantitative structure–activity relationship ,Allosteric regulation ,Quantitative Structure-Activity Relationship ,Computational biology ,Ligands ,01 natural sciences ,Cell Line ,Machine Learning ,Computers, Molecular ,03 medical and health sciences ,Structural bioinformatics ,0103 physical sciences ,Materials Chemistry ,Humans ,Physical and Theoretical Chemistry ,Spectroscopy ,Virtual screening ,Binding Sites ,010304 chemical physics ,Chemistry ,Computational Biology ,Computer Graphics and Computer-Aided Design ,Small molecule ,Transmembrane domain ,030104 developmental biology ,Docking (molecular) ,Drug Design ,Receptors, FSH ,Follicle-stimulating hormone receptor ,Hydrophobic and Hydrophilic Interactions ,Protein Binding - Abstract
Background The activation of follicle stimulating hormone receptor (FSHR) by FSH and the consequent downstream signaling activities are crucial for reproductive health. The role of FSHR in tumor progression as well as osteoporosis advancement has also been well established. Currently, steroid preparations of estrogen and progesterone are being used for managing fertility, in spite of the harmful side effects, as there has not been much success in identification of effective FSHR modulators. Structure-based drug design initiatives for identification of potent and specific FSHR modulators have been impeded due to the non-availability of the complete crystal structure of hFSHR complexed with FSH. Methods In this study, we have modeled the 3D structure of transmembrane domain (TMD) of hFSHR and identified molecules that demonstrate good binding affinity by virtual screening of drug-like library of compounds. The 3D structural and pharmacophoric features of the binders and non-binders obtained from virtual screening were further used to develop Support Vector Machine based classifier for TMD binding. Based on the observations from docking and SVM classification, a small molecule was identified for extensive MD simulations and in vitro assays for FSHR modulatory activity. Results The molecule selected based on docking score and SVM prediction was found to inhibit FSH-induced cAMP activity by 80% at 300 μM concentration. Conclusion The study proposes 1,3-diphenyl-1H-pyrazole-5-carboxylate as a promising scaffold for the design of new and potent FSHR allosteric inhibitors.
- Published
- 2019
36. Central residues of FSHβ (89-97) peptide are not critical for FSHR binding: Implications for peptidomimetic design
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Karishma Desai, Susan Idicula-Thomas, Vikas Dighe, Kaushiki S. Prabhudesai, Deepak Modi, Alessandro Contini, and Sahil Raje
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Models, Molecular ,endocrine system ,Peptidomimetic ,medicine.drug_class ,Clinical Biochemistry ,Pharmaceutical Science ,Peptide ,01 natural sciences ,Biochemistry ,Downregulation and upregulation ,Drug Discovery ,medicine ,Animals ,Humans ,Molecular Biology ,Granulosa cell proliferation ,chemistry.chemical_classification ,Alanine ,Binding Sites ,010405 organic chemistry ,Organic Chemistry ,Ovary ,Antagonist ,0104 chemical sciences ,Cell biology ,Androgen receptor ,010404 medicinal & biomolecular chemistry ,chemistry ,Estrogen ,Drug Design ,Molecular Medicine ,Receptors, FSH ,Female ,Peptidomimetics ,Follicle Stimulating Hormone ,Peptides - Abstract
In our previous study, we had identified a 9-mer peptide (FSHβ (89–97)) derived from seat belt loop of human FSHβ and demonstrated its ability to function as FSHR antagonist in vivo. Structure analysis revealed that the four central residues 91STDC94 within this peptide may not be critical for receptor binding. In the present study, 91STDC94 residues were substituted with alanine to generate ΔFSHβ 89–97(91STDC94/AAAA) peptide. Analogous to the parent peptide, ΔFSHβ 89–97(91STDC94/AAAA) peptide inhibited binding of iodinated FSH to rat FSHR and reduced FSH-induced cAMP production. The peptide could impede granulosa cell proliferation leading to reduction in FSH-mediated ovarian weight gain in immature female rats. In these rats, peptide administration further downregulated androgen receptor and estrogen receptor-alpha expression and upregulated estrogen receptor-beta expression. The results indicate that substitution of 91STDC94 with alanine did not significantly alter FSHR antagonist activity of FSHβ (89–97) peptide implying that these residues are not critical for FSH-FSHR interaction and can be replaced with non-peptidic moieties for development of more potent peptidomimetics.
- Published
- 2021
37. Enrichment analyses of diseases and pathways associated with precocious puberty using PrecocityDB
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Sameeksha Bhaye, Karishma Desai, Ram Shankar Barai, Khushal Pokar, Susan Idicula-Thomas, Mridula Sharma, and Indra Kundu
- Subjects
0301 basic medicine ,Databases, Factual ,Science ,Puberty, Precocious ,030209 endocrinology & metabolism ,Single-nucleotide polymorphism ,Comorbidity ,Disease ,Biology ,Polymorphism, Single Nucleotide ,Article ,Databases ,03 medical and health sciences ,0302 clinical medicine ,Insulin resistance ,medicine ,Humans ,Precocious puberty ,SNP ,Allele ,Gene ,Data Management ,Genetics ,Multidisciplinary ,Chromosome ,medicine.disease ,Computational biology and bioinformatics ,030104 developmental biology ,Medicine ,Endocrine Cells ,Signal Transduction - Abstract
Precocious puberty (PP) is an important endocrine disorder affecting children globally. Several genes, SNPs and comorbidities are reported to be associated with PP; however, this data is scattered across scientific literature and has not been systematically collated and analysed. In this study, we present PrecocityDB as the first manually curated online database on genes and their ontology terms, SNPs, and pathways associated with PP. A tool for visualizing SNP coordinates and allelic variation on each chromosome, for genes associated with PP is also incorporated in PrecocityDB. Pathway enrichment analysis of PP-associated genes revealed that endocrine and cancer-related pathways are highly enriched. Disease enrichment analysis indicated that individuals with PP seem to be highly likely to suffer from reproductive and metabolic disorders such as PCOS, hypogonadism, and insulin resistance. PrecocityDB is a useful resource for identification of comorbid conditions and disease risks due to shared genes in PP. PrecocityDB is freely accessible at http://www.precocity.bicnirrh.res.in. The database source code and content can be downloaded through GitHub (https://github.com/bic-nirrh/precocity).
- Published
- 2021
38. FSHR antagonists can trigger a PCOS-like state
- Author
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Faiza Hanif Waghu, Karishma Desai, Sumana Srinivasan, Kaushiki S. Prabhudesai, Vikas Dighe, Kareenhalli V. Venkatesh, and Susan Idicula-Thomas
- Subjects
Phosphatidylinositol 3-Kinases ,endocrine system ,Reproductive Medicine ,Urology ,Animals ,Humans ,Receptors, FSH ,Female ,Testosterone ,Follicle Stimulating Hormone ,Luteinizing Hormone ,Polycystic Ovary Syndrome ,Rats - Abstract
Over the recent years, FSHR has become an important target for development of fertility regulating agents, as impairment of FSH-FSHR interaction can lead to subfertility or infertility. In our previous study, we identified a 9-mer peptide (FSHβ (89–97)) that exhibited FSHR antagonist activity. The histopathological and biochemical observations indicated, in addition to FSHR antagonism, a striking resemblance to a PCOS-like state. These observations led us to hypothesize that use of FSHR antagonists can trigger a PCOS-like state. In the present study, to validate this hypothesis, we performed qRT-PCR validation using ovarian tissue samples from our previous study. Expression of three genes known to be differentially expressed in PCOS was evaluated and found to be similar to the PCOS state. To further test the hypothesis, theoretical simulations were carried out by using the human menstrual cycle model available in the literature. Model simulations for FSHR antagonism were indicative of increased testosterone levels, increased ratio of luteinizing hormone/follicle stimulating hormone, and stockpiling of secondary follicles, which are typical characteristics of PCOS. The findings of this study will be relevant while reviewing the utility of FSHR antagonists for fertility regulation and reproductive medicine. Abbreviations: FSH: Follicle-stimulating hormone; FSHR: Follicle-stimulating hormone receptor; cAMP: Cyclic adenosine 3’5’ monophosphate; PKA: Protein kinase A; PI3K: Phosphoinositide 3-kinase; PKB: protein kinase B; ERK1/2: Extracellular signal-regulated protein kinase 1/2; MAPK: Mitogen-activated protein kinases; T: testosterone; E2: estradiol; PCOS: Polycystic ovarian syndrome; LH: luteinizing hormone; Lhcgr: luteinizing hormone/choriogonadotropin receptor; CYP17A1: cytochrome P450 family 17 subfamily A member 1; Inhba: inhibin subunit beta A; qRT-PCR: Real-Time quantitative reverse transcription polymerase chain reaction; FSHβ: Follicle-stimulating hormone β subunit; Ct: Cycle threshold; Rn18s: Rattus norvegicus 18S ribosomal RNA
- Published
- 2021
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39. PCOSKBR2: a database of genes, diseases, pathways, and networks associated with polycystic ovary syndrome
- Author
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Susan Idicula-Thomas, Indra Kundu, Sameeksha Bhaye, Mridula Sharma, Ram Shankar Barai, and Khushal Pokar
- Subjects
0301 basic medicine ,Hub genes ,dbSNP ,endocrine system diseases ,Reproductive disorders ,MEDLINE ,lcsh:Medicine ,Single-nucleotide polymorphism ,Biology ,computer.software_genre ,Data mining algorithm ,Article ,Gene regulatory networks ,03 medical and health sciences ,Databases ,0302 clinical medicine ,KEGG ,lcsh:Science ,Gene ,Multidisciplinary ,Database ,lcsh:R ,Polycystic ovary ,030104 developmental biology ,030220 oncology & carcinogenesis ,lcsh:Q ,computer - Abstract
PolyCystic Ovary Syndrome KnowledgeBase (PCOSKBR2) is a manually curated database with information on 533 genes, 145 SNPs, 29 miRNAs, 1,150 pathways, and 1,237 diseases associated with PCOS. This data has been retrieved based on evidence gleaned by critically reviewing literature and related records available for PCOS in databases such as KEGG, DisGeNET, OMIM, GO, Reactome, STRING, and dbSNP. Since PCOS is associated with multiple genes and comorbidities, data mining algorithms for comorbidity prediction and identification of enriched pathways and hub genes are integrated in PCOSKBR2, making it an ideal research platform for PCOS. PCOSKBR2 is freely accessible at http://www.pcoskb.bicnirrh.res.in/.
- Published
- 2020
40. Membrane Interactome of a Recombinant Fragment of Human Surfactant Protein D Reveals GRP78 as a Novel Binding Partner in PC3, a Metastatic Prostate Cancer Cell Line
- Author
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Gargi Thakur, Gajanan Sathe, Indra Kundu, Barnali Biswas, Poonam Gautam, Saad Alkahtani, Susan Idicula-Thomas, Ravi Sirdeshmukh, Uday Kishore, and Taruna Madan
- Subjects
0301 basic medicine ,lcsh:Immunologic diseases. Allergy ,Male ,GRP78 ,surfactant protein D ,medicine.drug_class ,Immunology ,Collectin ,Monoclonal antibody ,Interactome ,Metastasis ,law.invention ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,law ,medicine ,Immunology and Allergy ,Humans ,Neoplasm Metastasis ,Endoplasmic Reticulum Chaperone BiP ,innate immunity ,Heat-Shock Proteins ,Original Research ,Chemistry ,Surfactant protein D ,Cell Membrane ,apoptosis ,Prostatic Neoplasms ,medicine.disease ,Pulmonary Surfactant-Associated Protein D ,prostate cancer ,Recombinant Proteins ,Cell biology ,Neoplasm Proteins ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer cell ,PC-3 Cells ,Recombinant DNA ,interactome analysis ,lcsh:RC581-607 ,signaling - Abstract
Data Availability Statement: The datasets presented in this study can be found in online repositories. The names of the repositories and accession number(s) can be found in the article/Supplementary Material (https://www.frontiersin.org/articles/10.3389/fimmu.2020.600660/full#h11). Copyright © 2021 Thakur, Sathe, Kundu, Biswas, Gautam, Alkahtani, Idicula-Thomas, Sirdeshmukh, Kishore and Madan. Surfactant protein-D (SP-D), a member of the collectin family has been shown to induce apoptosis in cancer cells. SP-D is composed of an N-terminal collagen-like domain and a calcium-dependent carbohydrate recognition domain (CRD). Recently, we reported that a recombinant fragment of human SP-D (rfhSP-D), composed of homotrimeric CRD region, induced intrinsic apoptotic pathway in prostate cancer cells. Here, we analyzed the membrane interactome of rfhSP-D in an androgen-independent prostate cancer cell line, PC3, by high resolution mass spectrometry and identified 347 proteins. Computational analysis of PPI network of this interactome in the context of prostate cancer metastasis and apoptosis revealed Glucose Regulated Protein of 78 kDa (GRP78) as an important binding partner of rfhSP-D. Docking studies suggested that rfhSP-D (CRD) bound to the substrate-binding domain of glycosylated GRP78. This was further supported by the observations that human recombinant GRP78 interfered with the binding of rfhSP-D to anti-SP-D polyclonal antibodies; GRP78 also significantly inhibited the binding of recombinant full-length human SP-D with a monoclonal antibody specific to the CRD in a dose-dependent manner. We conclude that the interaction with rfhSP-D is likely to interfere with the pro-survival signaling of GRP78. ICMR- National Institute for Research in Reproductive Health ICMR-NIRRH (Accession no. 921); ICMR- National Institute for Research in Reproductive Health ICMR-NIRRH-JRF; ICMR- National Institute for Research in Reproductive Health ICMR-SRF; Researchers Supporting Project (RSP-2020/26) King Saud University, Riyadh.
- Published
- 2020
41. A 5-mer peptide derived from hinge region of hFSHR can function as positive allosteric modulator in vivo
- Author
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Susan Idicula-Thomas, Vikas Dighe, Kaushiki S. Prabhudesai, and Muthu Sankar Aathi
- Subjects
0301 basic medicine ,endocrine system ,Allosteric modulator ,Biophysics ,030209 endocrinology & metabolism ,Peptide ,Leucine-rich repeat ,Molecular Dynamics Simulation ,Biochemistry ,Second Messenger Systems ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Allosteric Regulation ,Extracellular ,Cyclic AMP ,Animals ,Humans ,Receptor ,Granulosa cell proliferation ,Cell Proliferation ,chemistry.chemical_classification ,Granulosa Cells ,Chemistry ,Cell Biology ,Amino acid ,Cell biology ,Rats ,Molecular Docking Simulation ,Transmembrane domain ,030104 developmental biology ,HEK293 Cells ,Receptors, FSH ,Female ,Peptides - Abstract
Interaction of follicle stimulating hormone (FSH) with its cognate receptor (FSHR) is critical for maintaining reproductive health. FSHR has a large extracellular domain (ECD), composed of leucine rich repeats (LRRs) and hinge region, a transmembrane domain (TMD) and a short C-terminal domain (CTD). In this study, we have identified a short peptidic stretch in the hinge region (hFSHR(271-275)), through extensive computational modeling, docking and MD simulations, that is capable of independently interacting with the extracellular loops of FSHR(TMD). In vitro studies revealed that FSHR(271-275) peptide increased binding of [125I]-FSH to rat Fshr as well as FSH-induced cAMP production. Administration of FSHR(271-275) peptide in immature female rats significantly increased FSH-mediated ovarian weight gain and promoted granulosa cell proliferation. In summary, the results demonstrate that the synthetic peptide corresponding to amino acids 271-275 of hFSHR-hinge region stimulates FSH-FSHR interaction and behaves as positive allosteric modulator of FSHR. The study also lends evidence to the existing proposition that hinge region maintains the receptor in an inactive conformation in the absence of its ligand by engaging in intramolecular interactions with extracellular loops of TMD.
- Published
- 2020
42. PCOSKB
- Author
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Mridula, Sharma, Ram Shankar, Barai, Indra, Kundu, Sameeksha, Bhaye, Khushal, Pokar, and Susan, Idicula-Thomas
- Subjects
MicroRNAs ,Gene Expression Profiling ,Knowledge Bases ,Databases, Genetic ,Computational Biology ,Humans ,Disease ,Female ,Gene Regulatory Networks ,Polymorphism, Single Nucleotide ,Algorithms ,Polycystic Ovary Syndrome ,Signal Transduction - Abstract
PolyCystic Ovary Syndrome KnowledgeBase (PCOSKB
- Published
- 2020
43. A QSAR modeling approach for predicting myeloid antimicrobial peptides with high sequence similarity
- Author
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Ulka Gawde, Evans C. Coutinho, Anish Narasimhan Gomatam, Faiza Hanif Waghu, and Susan Idicula-Thomas
- Subjects
Models, Molecular ,Pore Forming Cytotoxic Proteins ,Quantitative structure–activity relationship ,Antimicrobial peptides ,Quantitative Structure-Activity Relationship ,Peptide ,Computational biology ,01 natural sciences ,Biochemistry ,Hemolysis ,Structure-Activity Relationship ,Similarity (network science) ,Drug Discovery ,Escherichia coli ,Humans ,Amino Acid Sequence ,Pharmacology ,chemistry.chemical_classification ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Rational design ,Reproducibility of Results ,Antimicrobial ,0104 chemical sciences ,Cathelicidins ,010404 medicinal & biomolecular chemistry ,Klebsiella pneumoniae ,Cheminformatics ,Pseudomonas aeruginosa ,Molecular Medicine - Abstract
Microbial resistance to conventional antibiotics has led to a surge in antimicrobial peptide (AMP) rational design initiatives that rely heavily on algorithms with good prediction accuracy and sensitivity. We present a quantitative structure-activity relationship (QSAR) approach for predicting activity of cathelicidins, an AMP family with broad-spectrum activity. The best multiple linear regression model built against Escherichia coli ATCC 25922 could accurately predict activity of three rationally designed peptides CP, DP, and Mapcon, having high sequence similarity. On further experimental validation of the rationally designed peptides, CP was found to exhibit high antimicrobial activity with negligible hemolysis. Here, we provide CP, an AMP with potential therapeutic applications and a family-based QSAR model for AMP prediction.
- Published
- 2019
44. Tubulin acetylation: A novel functional avenue for CDYL in sperm
- Author
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Veena Dalvi, Shobha Sonawane, Susan Idicula-Thomas, Priyanka Parte, Sushma Mylavaram, Sweta Parab, and Abhipriya Kishore
- Subjects
Male ,0301 basic medicine ,Axoneme ,macromolecular substances ,Flagellum ,Microtubules ,Chromodomain ,Rats, Sprague-Dawley ,03 medical and health sciences ,Tubulin ,Structural Biology ,Microtubule ,Animals ,030102 biochemistry & molecular biology ,biology ,Acetylation ,Cell Biology ,Lysine Acetyltransferases ,Sperm ,Rats ,Molecular Docking Simulation ,030104 developmental biology ,Biochemistry ,Sperm Tail ,Acetyltransferase ,biology.protein - Abstract
Motility in sperm is driven by the flagella, the principal component of which is the axoneme. The microtubules which make up the 9 + 2 axoneme are composed of heterodimers of alpha and beta tubulins and undergo several post-translational modifications. We have earlier reported that HDAC6 functions as tubulin deacetylase in sperm and has a role in sperm movement. While exploring the specific tubulin acetyltransferase (TAT) in sperm we observed the presence of Chromodomain Y-Like (CDYL), on the principal piece of rat spermatozoa which compelled us to explore its function in sperm. CDYL was observed to be colocalized with acetylated alpha-tubulin (Ac α Tubulin) in sperm flagella. Sperm axonemal fraction showed the presence of CDYL protein indicating its strong association with flagellar microtubules. Sequence alignment of CDYL chromo domain and Alpha tubulin acetyltransferase (αTAT1) revealed that of the 10 residues of αTAT1 known to be involved in α-tubulin binding, 5 residues were identical and 1 was conserved between the two proteins. Docking of CDYL chromo domain and α-tubulin showed that 6 of the 11 important binding residues of α-tubulin showed an interaction with CDYL chromo domain. The putative CDYL chromodomain –α-tubulin interaction was further confirmed by Microscale Thermophoresis. We further asserted the ability of recombinant CDYL and Sperm CDYL to acetylate soluble tubulin and microtubules in vitro. Acetylation of tubulin was increased over two fold in cells overexpressing CDYL. Thus our studies convincingly demonstrate the ability of CDYL to moonlight as a tubulin acetyltransferase. This article is protected by copyright. All rights reserved.
- Published
- 2017
45. A steady-state modeling approach for simulation of antimicrobial peptide-cell membrane interaction
- Author
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Kareenhalli V. Venkatesh, Susan Idicula-Thomas, Sumana Srinivasan, and Faiza Hanif Waghu
- Subjects
Models, Molecular ,Antimicrobial peptides ,Biophysics ,Peptide ,Cooperativity ,AMP binding ,Microbial Sensitivity Tests ,Biochemistry ,Cell membrane ,03 medical and health sciences ,medicine ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,030306 microbiology ,Systems Biology ,Cell Membrane ,Membrane Proteins ,Cell Biology ,Anti-Bacterial Agents ,Membrane ,medicine.anatomical_structure ,chemistry ,Steady state (chemistry) ,Saturation (chemistry) ,Antimicrobial Cationic Peptides ,Protein Binding - Abstract
Antimicrobial Peptides (AMPs) are host defense molecules that initiate microbial death by binding to the membrane. On membrane binding, AMPs undergo changes in conformation and aggregation state to enable killing action. Depending on the AMP and cell membrane characteristics, the nature of binding can be aggregating or non-aggregating, with high/low cooperativity, at single or multiple sites with high/low affinity leading to a unique killing action that needs to be studied individually. In the present study, a steady-state model that simulates AMP-membrane interaction was developed and was used to predict the mechanism of AMP binding. The predictions obtained from the model were validated with experimentally deciphered values available in literature. The model was further used to predict the mechanism for a set of designed AMPs with high sequence similarity to Myeloid Antimicrobial Peptide (MAP) family. Depending on the predicted mechanism, a unique half saturation constant and steepness of response (Hill coefficient) was obtained which was further validated with available data from literature. The model could reliably predict the mechanism, the half saturation constant and the Hill coefficient values. Further based on the analysis, it was observed that aggregation and oligomerization result in drastic killing action in a short range of peptide concentration owing to high Hill coefficient values. Mechanisms such as monomers binding at multiple sites with/without cooperativity result in antimicrobial activity at low half saturation constant though the killing action may not be steep. Thus, the methodology developed here can be used to develop hypothesis for studying AMP-membrane interaction mechanisms.
- Published
- 2019
46. Identification and in vivo validation of a 9-mer peptide derived from FSHβ with FSHR antagonist activity
- Author
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Alessandro Contini, Sahil Raje, Susan Idicula-Thomas, Ankita Dhamanaskar, Vikas Dighe, Kaushiki S. Prabhudesai, and Deepak Modi
- Subjects
endocrine system ,Physiology ,030209 endocrinology & metabolism ,Peptide ,Crystallography, X-Ray ,Biochemistry ,Homology (biology) ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Endocrinology ,Ovarian Follicle ,In vivo ,Animals ,chemistry.chemical_classification ,Granulosa Cells ,Estradiol ,Chemistry ,Ovary ,Antagonist ,Cell cycle ,In vitro ,Rats ,Cell biology ,Follicle Stimulating Hormone, beta Subunit ,Receptors, FSH ,Female ,Protein Structural Elements ,Folliculogenesis ,Oligopeptides ,Spermatogenesis ,030217 neurology & neurosurgery - Abstract
FSH-FSHR interaction is critical for folliculogenesis, spermatogenesis and progression of several cancers. Therefore, FSHR is an attractive target for fertility regulation and cancer therapeutics. Based on homology and structural analysis of hFSH-FSHR(ECD) complex, a minimal continuous stretch within FSHβ seat-belt loop (FSHβ (89-97)) was identified to be crucial for FSHR interaction. The ability of FSHβ (89-97) peptide to neutralize FSHR activity was evaluated by a panel of in vitro and in vivo experiments. The synthetic peptide significantly inhibited binding of [125I]-FSH to rat Fshr as well as FSH-induced cAMP production. In immature rats, FSHβ (89-97) peptide administration reduced FSH-mediated increase in ovarian weight. The peptide inhibited transition of follicles from pre-antral to antral stage and hindered the cell cycle progression of granulosa cells beyond G0/G1 phase. In adult rats, administration of the peptide inhibited estradiol synthesis and significantly perturbed folliculogenesis.
- Published
- 2020
47. PCOSKB: A KnowledgeBase on genes, diseases, ontology terms and biochemical pathways associated with PolyCystic Ovary Syndrome
- Author
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Susan Idicula-Thomas, Ram Shankar Barai, Shaini Joseph, and Rasika Bhujbalrao
- Subjects
0301 basic medicine ,Databases, Factual ,Biochemical Phenomena ,Protein Conformation ,Knowledge Bases ,Gene regulatory network ,MEDLINE ,Single-nucleotide polymorphism ,Comorbidity ,Scientific literature ,Biology ,Bioinformatics ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Polymorphism (computer science) ,Genetics ,medicine ,Humans ,Database Issue ,Gene Regulatory Networks ,Gene ,medicine.disease ,Polycystic ovary ,Gene Ontology ,030104 developmental biology ,Mutation ,Female ,Databases, Chemical ,Polycystic Ovary Syndrome - Abstract
Polycystic ovary syndrome (PCOS) is one of the major causes of female subfertility worldwide and ≈ 7-10% of women in reproductive age are affected by it. The affected individuals exhibit varying types and levels of comorbid conditions, along with the classical PCOS symptoms. Extensive studies on PCOS across diverse ethnic populations have resulted in a plethora of information on dysregulated genes, gene polymorphisms and diseases linked to PCOS. However, efforts have not been taken to collate and link these data. Our group, for the first time, has compiled PCOS-related information available through scientific literature; cross-linked it with molecular, biochemical and clinical databases and presented it as a user-friendly, web-based online knowledgebase for the benefit of the scientific and clinical community. Manually curated information on associated genes, single nucleotide polymorphisms, diseases, gene ontology terms and pathways along with supporting reference literature has been collated and included in PCOSKB (http://pcoskb.bicnirrh.res.in).
- Published
- 2015
48. PBIT: Pipeline Builder for Identification of drug Targets for infectious diseases
- Author
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Mohammed Husain Bharmal, Vinit Shetty, Gauri Shende, Ram Shankar Barai, Susan Idicula-Thomas, and Harshala Haldankar
- Subjects
0301 basic medicine ,Statistics and Probability ,Drug ,030103 biophysics ,Proteome ,Computer science ,In silico ,media_common.quotation_subject ,Bioinformatics ,Communicable Diseases ,Biochemistry ,03 medical and health sciences ,Human gut ,Candida albicans ,Drug Discovery ,Human proteome project ,Humans ,Computer Simulation ,Molecular Biology ,media_common ,Supplementary data ,Internet ,Microbiota ,Computational Biology ,Pipeline (software) ,Computer Science Applications ,Computational Mathematics ,030104 developmental biology ,Computational Theory and Mathematics ,Identification (biology) - Abstract
Summary PBIT (Pipeline Builder for Identification of drug Targets) is an online webserver that has been developed for screening of microbial proteomes for critical features of human drug targets such as being non-homologous to human proteome as well as the human gut microbiota, essential for the pathogen’s survival, participation in pathogen-specific pathways etc. The tool has been validated by analyzing 57 putative targets of Candida albicans documented in literature. PBIT integrates various in silico approaches known for drug target identification and will facilitate high-throughput prediction of drug targets for infectious diseases, including multi-pathogenic infections. Availability and Implementation PBIT is freely accessible at http://www.pbit.bicnirrh.res.in/. Supplementary information Supplementary data are available at Bioinformatics online.
- Published
- 2016
49. Effect of diversity in gp41 membrane proximal external region of primary HIV-1 Indian subtype C sequences on interaction with broadly neutralizing antibodies 4E10 and 10E8
- Author
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Vidya S. Nagar, Priya Patil, Vainav Patel, Jyoti Sutar, Atmaram H. Bandivdekar, Jayanta Bhattacharya, Dhanashree D. Jagtap, Bhalachandra Kulkarni, Nitin Hingankar, Suprit Deshpande, Susan Idicula-Thomas, Archana Sonawani, and Varsha Padwal
- Subjects
Adult ,Male ,Cancer Research ,Human immunodeficiency virus (HIV) ,India ,HIV Infections ,HIV Antibodies ,Gp41 ,medicine.disease_cause ,Deep sequencing ,Neutralization ,DNA sequencing ,Epitope ,Epitopes ,03 medical and health sciences ,Meta-Analysis as Topic ,Neutralization Tests ,Virology ,medicine ,Humans ,Child ,030304 developmental biology ,0303 health sciences ,biology ,030306 microbiology ,Haplotype ,Genetic Variation ,High-Throughput Nucleotide Sequencing ,Middle Aged ,HIV Envelope Protein gp41 ,Molecular Docking Simulation ,Infectious Diseases ,HIV-1 ,biology.protein ,Female ,Antibody ,Broadly Neutralizing Antibodies - Abstract
Human Immunodeficiency Virus-1 Clade C (HIV-1C) dominates the AIDS epidemic in India, afflicting 2.1 million individuals within the country and more than 15 million people worldwide. Membrane proximal external region (MPER) is an attractive target for broadly neutralizing antibody (bNAb) based therapies. However, information on MPER sequence diversity from India is meagre due to limited sampling of primary viral sequences. In the present study, we examined the variation in MPER of HIV-1C from 24 individuals in Mumbai, India by high throughput sequencing of uncultured viral sequences. Deep sequencing of MPER (662-683; HXB2 envelope amino acid numbering) allowed quantification of intra-individual variation up to 65% at positions 662, 665, 668, 674 and 677 within this region. These variable positions included contact sites targeted by bNAbs 2F5, Z13e1, 4E10 as well as 10E8. Both major and minor epitope variants i.e. 'haplotypes' were generated for each sample dataset. A total of 23, 34 and 25 unique epitope haplotypes could be identified for bNAbs 2F5, Z13e1 and 4E10/10E8 respectively. Further analysis of 4E10 and 10E8 epitopes from our dataset and meta-analysis of previously reported HIV-1 sequences from India revealed 26 epitopes (7 India-specific), heretofore untested for neutralization sensitivity. Peptide-Ab docking predicted 13 of these to be non-binding to 10E8. ELISA, Surface Plasmon Resonance and peptide inhibition of HIV-1 neutralization assays were then performed which validated predicted weak/non-binding interactions for peptides corresponding to six of these epitopes. These results highlight the under-representation of 10E8 non-binding HIV-1C MPER sequences from India. Our study thus underscores the need for increased surveillance of primary circulating envelope sequences for development of efficacious bNAb-based interventions in India.
- Published
- 2019
50. Evaluation of 4-thiazolidinone derivatives as potential reverse transcriptase inhibitors against HIV-1 drug resistant strains
- Author
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Srikanth Tripathy, Dipen Desai, Ramesh S. Paranjape, Smita Kulkarni, Nandini Makwana, Vanangamudi Murugesan, Seturam B. Katti, Rahul K. Suryawanshi, Devidas N. Chaturbhuj, Susan Idicula-Thomas, Archana Sonawani, and Sushama Jadhav
- Subjects
Nevirapine ,Anti-HIV Agents ,In silico ,Human immunodeficiency virus (HIV) ,HIV Infections ,Drug resistance ,medicine.disease_cause ,01 natural sciences ,Biochemistry ,Cell Line ,Structure-Activity Relationship ,Drug Discovery ,Drug Resistance, Viral ,medicine ,Humans ,Molecular Biology ,IC50 ,Strain (chemistry) ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Virology ,Reverse transcriptase ,In vitro ,HIV Reverse Transcriptase ,0104 chemical sciences ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,HIV-1 ,Leukocytes, Mononuclear ,Reverse Transcriptase Inhibitors ,Thiazolidines ,medicine.drug - Abstract
Rapid emergence of drug resistance is crucial in management of HIV infection limiting implementation of efficacious drugs in the ART regimen. Designing new molecules against HIV drug resistant strains is utmost essential. Based on the anti-HIV-1 activity, we selected four 4-thiazolidinone derivatives (S009-1908, S009-1909, S009-1911, S009-1912) and studied their interaction with reverse transcriptase (RT) from a panel of 10 clinical isolates (8 nevirapine resistant and two susceptible) using in silico methods, and inhibition pattern using in vitro cell based assays. On the basis of binding affinity observed in in silico analysis, 2-(2-chloro-6-nitrophenyl)-3-(4, 6-dimethylpyridin-2-yl) thiazolidin-4-one (S009-1912) was identified as the lead molecule followed by S009-1908, S009-1909 and S009-1911. The in vitro activity against the same panel was assessed using TZM-bl assay (IC50: 0.4–11.44 µg/ml, TI: 4–126) and subsequently in PBMC assay against a nevirapine resistant clinical isolate (IC50: 0.8–6.65 µg/ml, TI: 8.31–11.43) and standard strain from NIH ARRRP (IC50: 0.95–3.6 µg/ml, TI: 9–26). The study shows analogue with pyrimidin-2-yl amino substitution at N-3 position of thiazolidin-4-one ring (S009-1908, S009-1909, S009-1911) exhibited enhanced activity as compared to pyridin-2-yl substituted derivatives (S009-1912), suggesting the use 4-thiazolidinones for developing potent inhibitors against HIV-1 drug resistant strains.
- Published
- 2017
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