Search

A review on a medicinal plant belong to family Labiatae has been made in the Kingdom of Saudi Arabia. Among the reported flora in the Kingdom of Saudi Arabia, Labiatae family has the highest species. A total of 23 species of Labiatae family has been reported with high medicinal value. A detail review on 12 species of Labiatae family had done to know their phytochemical constituents, medicinal uses and pharmacological properties. In this review we also explore the total chemical constituents present in each plant with a unique list of 3D chemical structures. (E)-2-Hexenal, 1,8-Cineole, Bicyclogermacrene, Borneol, Bornyl acetate, Bulnesol, Caffeic acid, Camphene, Camphor, Eugenol, Gallic acid, Quercetin, Terpinene, Thymol, etc are the important constituent in these 12 species of Labiatae family. This study also shows that Marrubium vulgare L, Ocimum basilicum L, Origanum majorana and Otostegia fruticosa plants had reported with many medicinal uses and pharmacological properties. Medicinal constituents include the highest phenolic, flavonoid content and strong aromatic essential oil. Further scientific investigations on these 12 species are needed to explore toxicity and clinical efficacy and as well as to explore the therapeutic effects of major secondary metabolites. The summarized information from the current review may be a useful tool for researchers to carry out further study and explore other scientific aspects of the herbs.

In this study, an efficient microalgal strain SD07 was isolated from pond wastewater and identified as Scenedesmus sp. using the 18S rRNA gene sequence analysis. The strain SD07 was grown in a variety of concentrations (25-100%) of municipal wastewater. Scenedesmus sp. strain SD07 grown in 75% diluted wastewater produced a higher amount of biomass (1.93 ± 0.10 g L

Breast cancer type 1 susceptibility protein (BRCA1) is closely related to the BRCA2 (breast cancer type 2 susceptibility protein) and BARD1 (BRCA1-associated RING domain-1) proteins. The homodimers were formed through their RING fingers; however they form more compact heterodimers preferentially, influencing BRCA1 residues 1-109 and BARD1 residues 26-119. We implemented an integrative computational pipeline to screen all the mutations in BRCA1 and identify the most significant mutations influencing the Protein-Protein Interactions (PPI) in the BRCA1-BARD1 protein complex. The amino acids involved in the PPI regions were identified from the PDBsum database with the PDB ID: 1JM7. We screened 2118 missense mutations in BRCA1 and none in BARD1 for pathogenicity and stability and analyzed the amino acid sequences for conserved residues. We identified the most significant mutations from these screenings as V11G, M18K, L22S, and T97R positioned in the PPI regions of the BRCA1-BARD1 protein complex. We further performed protein-protein docking using the ZDOCK server. The native protein-protein complex showed the highest binding score of 2118.613, and the V11G mutant protein complex showed the least binding score of 1992.949. The other three mutation protein complexes had binding scores between the native and V11G protein complexes. Finally, a molecular dynamics simulation study using GROMACS was performed to comprehend changes in the BRCA1-BARD1 complex's binding pattern due to the mutation. From the analysis, we observed the highest deviation with lowest compactness and a decrease in the intramolecular h-bonds in the BRCA1-BARD1 protein complex with the V11G mutation compared to the native complex or the complexes with other mutations.

An increase in the fast blood glucose (FBG) levels has been linked to an increased risk of developing a chronic condition, type 2 diabetes (T2D). The mutation in the G6PC2 gene was identified to have a lead role in the modulation of FBG levels. The abnormal regulation of this enzyme influences glucose-stimulated insulin secretion (GSIS), which controls the insulin levels corresponding to the system's glucose level. This study focuses on the mutations at the G6PC2 gene, which cause the variation from normal expression levels and increase the risk of T2D. We examined the non-synonymous single nucleotide polymorphisms (nsSNPs) present in the G6PC2 and subjected them to pathogenicity, stability, residue conservation, and membrane simulation. The individual representation of surrounding amino acids in the mutant (I63T) model showed the loss of hydrophobic interactions compared to the native G6PC2. In addition, the trajectory results from the membrane simulation exhibited reduced stability, and the least compactness was identified for the I63T mutant model. Our study shed light on the structural and conformational changes at the transmembrane region due to the I63T mutation in G6PC2. Additionally, the Gibbs free energy landscape analysis against the two principal components showed structural differences and decreased the conformational stability of the I63T mutant model compared to the native. Like those presented in this study, dynamical simulations may indeed be crucial to comprehending the structural insights of G6PC2 mutations in cardiovascular-associated mortality and T2D.

Breast cancer type 1 susceptibility protein (BRCA1) is closely related to the BRCA2 (breast cancer type 2 susceptibility protein) and BARD1 (BRCA1-associated RING domain-1) proteins. The homodimers were formed through their RING fingers; however they form more compact heterodimers preferentially, influencing BRCA1 residues 1-109 and BARD1 residues 26-119. We implemented an integrative computational pipeline to screen all the mutations in BRCA1 and identify the most significant mutations influencing the Protein-Protein Interactions (PPI) in the BRCA1-BARD1 protein complex. The amino acids involved in the PPI regions were identified from the PDBsum database with the PDB ID: 1JM7. We screened 2118 missense mutations in BRCA1 and none in BARD1 for pathogenicity and stability and analyzed the amino acid sequences for conserved residues. We identified the most significant mutations from these screenings as V11G, M18K, L22S, and T97R positioned in the PPI regions of the BRCA1-BARD1 protein complex. We further performed protein-protein docking using the ZDOCK server. The native protein-protein complex showed the highest binding score of 2118.613, and the V11G mutant protein complex showed the least binding score of 1992.949. The other three mutation protein complexes had binding scores between the native and V11G protein complexes. Finally, a molecular dynamics simulation study using GROMACS was performed to comprehend changes in the BRCA1-BARD1 complex's binding pattern due to the mutation. From the analysis, we observed the highest deviation with lowest compactness and a decrease in the intramolecular h-bonds in the BRCA1-BARD1 protein complex with the V11G mutation compared to the native complex or the complexes with other mutations. 2022 Elsevier Inc. This work was supported by Qatar University Grant# QUST-2-CHS-2019-3. Scopus

FMS-like tyrosine kinase 3 (FLT3) gene mutations have been found in more than one-third of Acute Myeloid Leukemia (AML) cases. The most common point mutation in FLT3 occurs at the 835th residue (D835A/E/F/G/H/I/N/V/Y), in the activation loop region. The D835 residue is critical in maintaining FLT3 inactive conformation, these mutations might influence the interaction with clinically approved AML inhibitors used to treat the AML. The molecular mechanism of each of these mutations and their interactions with AML inhibitors at the atomic level is still unknown. In this manuscript, we have investigated the structural consequence of native and mutant FLT-3 proteins and their molecular mechanisms at the atomic level, using molecular dynamics simulations (MDS). In addition, we use the molecular docking method to investigate the binding pattern between the FLT-3 protein and AML inhibitors upon mutations. This study apparently elucidates that, due to mutations in the D835, the FLT-3 structure loses its conformation and becomes more flexible compared to the native FLT3 protein. These structural changes are suggested to contribute to the relapse and resistance responses to AML inhibitors. Identifying the effects of FLT3 at the molecular level will aid in developing a personalized therapeutic strategy for treating patients with FLT-3-associated AML.

Artificial intelligence (AI) proves to have enormous potential in many areas of healthcare including research and chemical discoveries. Using large amounts of aggregated data, the AI can discover and learn further transforming these data into "usable" knowledge. Being well aware of this, the world's leading pharmaceutical companies have already begun to use artificial intelligence to improve their research regarding new drugs. The goal is to exploit modern computational biology and machine learning systems to predict the molecular behaviour and the likelihood of getting a useful drug, thus saving time and money on unnecessary tests. Clinical studies, electronic medical records, high-resolution medical images, and genomic profiles can be used as resources to aid drug development. Pharmaceutical and medical researchers have extensive data sets that can be analyzed by strong AI systems. This review focused on how computational biology and artificial intelligence technologies can be implemented by integrating the knowledge of cancer drugs, drug resistance, next-generation sequencing, genetic variants, and structural biology in the cancer precision drug discovery. Published version

Lysinuric protein intolerance (LPI) is a rare, yet inimical, genetic disorder characterized by the paucity of essential dibasic amino acids in the cells. Amino acid transporter y+LAT-1 interacts with 4F2 cell-surface antigen heavy chain to transport the required dibasic amino acids. Mutation in y+LAT-1 is rumored to cause LPI. However, the underlying pathological mechanism is unknown, and, in this analysis, we investigate the impact of point mutation in y+LAT-1's interaction with 4F2 cell-surface antigen heavy chain in causing LPI. Using an efficient and extensive computational pipeline, we have isolated M50K and L334R single-nucleotide polymorphisms to be the most deleterious mutations in y+LAT-1s. Docking of mutant y+LAT-1 with 4F2 cell-surface antigen heavy chain showed decreased interaction compared with native y+LAT-1. Further, molecular dynamic simulation analysis reveals that the protein molecules increase in size, become more flexible, and alter their secondary structure upon mutation. We believe that these conformational changes because of mutation could be the reason for decreased interaction with 4F2 cell-surface antigen heavy chain causing LPI. Our analysis gives pathological insights about LPI and helps researchers to better understand the disease mechanism and develop an effective treatment strategy.

In this study, two proficient Cadmium (Cd) resistant and plant growth-promoting actinobacterial strains were isolated from metal-polluted soils and identified as Streptomyces sp. strain RA04 and Nocardiopsis sp. strain RA07. Multiple abiotic stress tolerances were found in these two actinobacterial strains, including Cd stress (CdS), drought stress (DS) and high-temperature stress (HTS). Both actinobacterial strains exhibited multifarious plant growth-promoting (PGP) traits such as phosphate solubilization, and production of indole-3-acetic acid, siderophores and 1-aminocyclopropane-1-carboxylate deaminase under CdS, DS and HTS conditions. The inoculation of strains RA04 and RA07 significantly increased Sorghum bicolor growth and photosynthetic pigments under CdS, DS, HTS, CdS + DS and CdS + HTS conditions as compared to their respective uninoculated plants. The actinobacterial inoculants reduced malondialdehyde concentration and enhanced antioxidant enzymes in plants cultivated under various abiotic stress conditions, indicating that actinobacterial inoculants reduced oxidative damage. Furthermore, strains RA04 and RA07 enhanced the accumulation of Cd in plant tissues and the translocation of Cd from root to shoot under CdS, CdS + DS and CdS + HTS treatments as compared to their respective uninoculated plants. These findings suggest that RA04 and RA07 strains could be effective bio-inoculants to accelerate phytoremediation of Cd polluted soil even in DS and HTS conditions.

Idiopathic pulmonary fibrosis (IPF) is a rare yet crucial persistent lung disorder that actuates scarring of lung tissues, which makes breathing difficult. Smoking, environmental pollution, and certain viral infections could initiate lung scarring. However, the molecular mechanism involved in IPF remains elusive. To develop an efficient therapeutic arsenal against IPF, it is vital to understand the pathology and deviations in biochemical pathways that lead to disorder. In this study, we availed network analysis and other computational pipelines to delineate the prominent membrane proteins as diagnostic biomarkers and therapeutic targets for IPF. This study yielded a significant role of glycosaminoglycan binding, endothelin, and GABA-B receptor signaling pathway in IPF pathogenesis. Furthermore, ADCY8, CRH, FGB, GPR17, MCHR1, NMUR1, and SAA1 genes were found to be immensely involved with IPF, and the enrichment pathway analysis suggests that most of the pathways were corresponding to membrane transport and signal transduction functionalities. This analysis could help in better understanding the molecular mechanism behind IPF to develop an efficient therapeutic target or biomarkers for IPF.

Idiopathic pulmonary fibrosis (IPF) is a rare yet crucial persistent lung disorder that actuates scarring of lung tissues, which makes breathing difficult. Smoking, environmental pollution, and certain viral infections could initiate lung scarring. However, the molecular mechanism involved in IPF remains elusive. To develop an efficient therapeutic arsenal against IPF, it is vital to understand the pathology and deviations in biochemical pathways that lead to disorder. In this study, we availed network analysis and other computational pipelines to delineate the prominent membrane proteins as diagnostic biomarkers and therapeutic targets for IPF. This study yielded a significant role of glycosaminoglycan binding, endothelin, and GABA-B receptor signaling pathway in IPF pathogenesis. Furthermore, ADCY8, CRH, FGB, GPR17, MCHR1, NMUR1, and SAA1 genes were found to be immensely involved with IPF, and the enrichment pathway analysis suggests that most of the pathways were corresponding to membrane transport and signal transduction functionalities. This analysis could help in better understanding the molecular mechanism behind IPF to develop an efficient therapeutic target or biomarkers for IPF.

Interferon regulatory factor 1 (IRF-1) plays a vital role in cell proliferation and cell differentiation by acting as a tumor suppressor gene and its role is linked to various types of cancers, including leukemia and pre-leukemia myelodysplasia. Mutations in the coding region of the IRF-1 are likely to influence the IRF-1 and its DNA binding affinity. The molecular mechanism of the DNA recognition with the IRF-1 protein upon mutations is still unknown. In this study, we have elucidated the structural and functional behavior of the wild-type and mutant (K75E and E222K) IRF-1 proteins and their corresponding molecular mechanisms with DNA recognition at the molecular level, using molecular dynamics simulations. Furthermore, we also applied the docking approach to examine the binding between the IRF-1 protein and DNA upon mutations. This study evidently explains that, due to mutations, the IRF-1 structure loses its stability and becomes more flexible than the wild-type protein. This structural loss might affect IRF-1-DNA interaction and lead to the inhibition of cancer suppression. Identifying the effects of IRF-1 at the molecular level will be beneficial for designing drugs for IRF-1 associated cancers. These drugs should be designed so that they can help reactivate the IRF-1 function, by increasing the transcriptional activity, to treat leukemia.

Introduction: The extreme health and economic problems in the world due to the SARS-CoV-2 infection have led to an urgent need to identify potential drug targets for treating coronavirus disease 2019 (COVID-19). The present state-of-the-art tool-based screening was targeted to identify drug targets among clinically approved drugs by uncovering SARS-CoV-2 helicase inhibitors through molecular docking analysis. Material and methods: Helicase is a vital viral replication enzyme, which unwinds nucleic acids and separates the double-stranded nucleic acids into single-stranded nucleic acids. Hence, the SARS-CoV-2 helicase protein 3D structure was predicted, validated, and used to screen the druggable targets among clinically approved drugs such as protease inhibitor, nucleoside reverse transcriptase inhibitor, and non-nucleoside reverse transcriptase inhibitors, used to treat HIV infection using molecular docking analysis. Results: Interaction with SARS-CoV-2 helicase, approved drugs, vapreotide (affinity: -12.88; S score: -9.84 kcal/mol), and atazanavir (affinity: -11.28; S score: -9.32 kcal/mol), approved drugs for treating AIDS-related diarrhoea and HIV infection, respectively, are observed with significantly low binding affinity and MOE score or binding free energy. The functional binding pockets of the clinically approved drugs on SARS-CoV-2 helicase protein molecule suggest that vapreotide and atazanavir may interrupt the activities of the SARS-CoV-2 helicase. Conclusions: The study suggests that vapreotide may be a choice of drug for wet lab studies to inhibit the infection of SARS-CoV-2.

Sjögren-Larsson syndrome (SLS) is an autoimmune disorder inherited in an autosomal recessive pattern. To date, 80 missense mutations have been identified in association with the Aldehyde Dehydrogenase 3 Family Member A2 (ALDH3A2) gene causing SLS. Disruption of the function of ALDH3A2 leads to excessive accumulation of fat in the cells, which interferes with the normal function of protective membranes or materials that are necessary for the body to function normally. We retrieved 54 missense mutations in the ALDH3A2 from the OMIM, UniProt, dbSNP, and HGMD databases that are known to cause SLS. These mutations were examined with various in silico stability tools, which predicted that the mutations p.S308N and p.R423H that are located at the protein-protein interaction domains are the most destabilizing. Furthermore, to determine the atomistic-level differences within the protein-protein interactions owing to mutations, we performed macromolecular simulation (MMS) using GROMACS to validate the motion patterns and dynamic behavior of the biological system. We found that both mutations (p.S380N and p.R423H) had significant effects on the protein-protein interaction and disrupted the dimeric interactions. The computational pipeline provided in this study helps to elucidate the potential structural and functional differences between the ALDH3A2 native and mutant homodimeric proteins, and will pave the way for drug discovery against specific targets in the SLS patients.

Sjogren–Larsson syndrome (SLS) is an autoimmune disorder inherited in an autosomal recessive pattern. To date, 80 missense mutations have been identified in association with the Aldehyde Dehydrogenase 3 Family Member A2 (ALDH3A2) gene causing SLS. Disruption of the function of ALDH3A2 leads to excessive accumulation of fat in the cells, which interferes with the normal function of protective membranes or materials that are necessary for the body to function normally. We retrieved 54 missense mutations in the ALDH3A2 from the OMIM, UniProt, dbSNP, and HGMD databases that are known to cause SLS. These mutations were examined with various in silico stability tools, which predicted that the mutations p.S308N and p.R423H that are located at the protein-protein interaction domains are the most destabilizing. Furthermore, to determine the atomistic-level differences within the protein-protein interactions owing to mutations, we performed macromolecular simulation (MMS) using GROMACS to validate the motion patterns and dynamic behavior of the biological system. We found that both mutations (p.S380N and p.R423H) had significant effects on the protein-protein interaction and disrupted the dimeric interactions. The computational pipeline provided in this study helps to elucidate the potential structural and functional differences between the ALDH3A2 native and mutant homodimeric proteins, and will pave the way for drug discovery against specific targets in the SLS patients.

COVID-19 is an infectious and pathogenic viral disease caused by SARS-CoV-2 that leads to septic shock, coagulation dysfunction, and acute respiratory distress syndrome. The spreading rate of SARS-CoV-2 is higher than MERS-CoV and SARS-CoV. The receptor-binding domain (RBD) of the Spike-protein (S-protein) interacts with the human cells through the host angiotensin-converting enzyme 2 (ACE2) receptor. However, the molecular mechanism of pathological mutations of S-protein is still unclear. In this perspective, we investigated the impact of mutations in the S-protein and their interaction with the ACE2 receptor for SAR-CoV-2 viral infection. We examined the stability of pathological nonsynonymous mutations in the S-protein, and the binding behavior of the ACE2 receptor with the S-protein upon nonsynonymous mutations using the molecular docking and MM_GBSA approaches. Using the extensive bioinformatics pipeline, we screened the destabilizing (L8V, L8W, L18F, Y145H, M153T, F157S, G476S, L611F, A879S, C1247F, and C1254F) and stabilizing (H49Y, S50L, N501Y, D614G, A845V, and P1143L) nonsynonymous mutations in the S-protein. The docking and binding free energy (ddG) scores revealed that the stabilizing nonsynonymous mutations show increased interaction between the S-protein and the ACE2 receptor compared to native and destabilizing S-proteins and that they may have been responsible for the virulent high level. Further, the molecular dynamics simulation (MDS) approach reveals the structural transition of mutants (N501Y and D614G) S-protein. These insights might help researchers to understand the pathological mechanisms of the S-protein and provide clues regarding mutations in viral infection and disease propagation. Further, it helps researchers to develop an efficient treatment approach against this SARS-CoV-2 pandemic.

In this study, Chlorella sp., Scenedesmus sp., and their consortium were used for the biorefinery approach. The algal consortium (Chlorella sp. + Scenedesmus sp.) grown well in 75% diluted wastewater, and obtained the highest biomass (1.78 g L−1), chlorophyll (27.03 μg mL−1), protein (175 μg mL−1) and lipid content (34.83% dry cell weight). Algal consortium showed mainly 51.75% of palmitic acid and 35.45% of oleic acid in the lipids. The removal of nitrate, ammonium, phosphate, chemical oxygen demand, total organic carbon and total nitrogen in 75% diluted wastewater by algal consortium were 96%, 98%, 95%, 83%, 86% and 94%, respectively. Moreover, deoiled algal biomass (DAB) waste used as a biofertilizer combined with inorganic fertilizer resulted in the grater improvement of Solanum lycopersicum shoot length (44%), root length (89%), fresh weight (95%), dry weight (53%), macro and micro-nutrients (N 61%, P 179%, K 71%, Ca 38%, Mg 26% and Fe 11%), and tomato yield (174%) as compared to control treatment. Our results indicate that the use of consortium is not only a potential bioresource for wastewater treatment and biodiesel production but also the DAB waste is an effective biofertilizer for sustainable agriculture production.

In this study, finger millet straw (FMS) was utilized for the production of Polyhydroxybutyrate (PHB) by Bacillus megaterium strain CAM12. Ultrasound-assisted alkaline (NaOH) pretreatment of FMS under optimized conditions followed by enzymatic saccharification resulted in the maximum delignification (72%), hydrolysis yield (84%), glucose yield (86%) and xylose yield (61%). The effects of different pH, temperature, incubation period, inoculum concentration, agitation speed and FMS enzymatic hydrolysates concentration were investigated to improve the PHB production. Under optimized conditions, strain CAM12 used the FMS hydrolysates as the sole carbon source for their growth and produced 8.31 g L−1 of PHB. The extracted polymer on Fourier transform infrared (FTIR), X-ray diffraction (XRD) and Nuclear magnetic resonance (NMR) analyses were confirmed to be PHB. These results suggest the potential of combined ultrasound and alkaline pretreated FMS hydrolysates as a promising feedstock for PHB production.

Oculocutaneous albinism type IV (OCA4) is an autosomal recessive inherited disorder which is characterized by reduced biosynthesis of melanin pigmentation in skin, hair, and eyes and caused by the genetic mutations in the membrane-associated transporter protein (MATP) encoded by SLC45A2 gene. The MATP protein consists of 530 amino acids which contains 12 putative transmembrane domains and plays an important role in pigmentation and probably functions as a membrane transporter in melanosomes. We scrutinized the most OCA4 disease-associated mutation and their structural consequences on SLC45A2 gene. To understand the atomic arrangement in 3D space, the native and mutant structures were modeled. Further the structural behavior of native and mutant MATP protein was investigated by molecular dynamics simulation (MDS) approach in explicit lipid and water background. We found Y317C as the most deleterious and disease-associated SNP on SLC45A2 gene. In MDS, mutations in MATP protein showed loss of stability and became more flexible, which alter its structural conformation and function. This phenomenon has indicated a significant role in inducing OCA4. Our study explored the understanding of molecular mechanism of MATP protein upon mutation at atomic level and further helps in the field of pharmacogenomics to develop a personalized medicine for OCA4 disorder. J. Cell. Biochem. 117: 2608-2619, 2016. © 2016 Wiley Periodicals, Inc.

Filamins (FLN) are a family of actin-binding proteins involved in regulating the cytoskeleton and signaling phenomenon by developing a network with F-actin and FLN-binding partners. The FLN family comprises three conserved isoforms in mammals: FLNA, FLNB, and FLNC. FLNB is a multidomain monomer protein with domains containing an actin-binding N-terminal domain (ABD 1&ndash, 242), encompassing two calponin-homology domains (assigned CH1 and CH2). Primary variants in FLNB mostly occur in the domain (CH2) and surrounding the hinge-1 region. The four autosomal dominant disorders that are associated with FLNB variants are Larsen syndrome, atelosteogenesis type I (AOI), atelosteogenesis type III (AOIII), and boomerang dysplasia (BD). Despite the intense clustering of FLNB variants contributing to the LS-AO-BD disorders, the genotype-phenotype correlation is still enigmatic. In silico prediction tools and molecular dynamics simulation (MDS) approaches have offered the potential for variant classification and pathogenicity predictions. We retrieved 285 FLNB missense variants from the UniProt, ClinVar, and HGMD databases in the current study. Of these, five and 39 variants were located in the CH1 and CH2 domains, respectively. These variants were subjected to various pathogenicity and stability prediction tools, evolutionary and conservation analyses, and biophysical and physicochemical properties analyses. Molecular dynamics simulation (MDS) was performed on the three candidate variants in the CH2 domain (W148R, F161C, and L171R) that were predicted to be the most pathogenic. The MDS analysis results showed that these three variants are highly compact compared to the native protein, suggesting that they could affect the protein on the structural and functional levels. The computational approach demonstrates the differences between the FLNB mutants and the wild type in a structural and functional context. Our findings expand our knowledge on the genotype-phenotype correlation in FLNB-related LS-AO-BD disorders on the molecular level, which may pave the way for optimizing drug therapy by integrating precision medicine.

Synthetic glucocorticoids (GC) are the mainstay therapy for treatment of acute and chronic inflammatory disorders. Due to the high adverse effects associated with long-term use, GC pharmacology has focused since the nineties on more selective GC ligand-binding strategies, classified as selective glucocorticoid receptor (GR) agonists (SEGRAs) or selective glucocorticoid receptor modulators (SEGRMs). In the current study, GSK866 analogs with electrophilic covalent-binding warheads were developed with potential SEGRA properties to improve their clinical safety profile for long-lasting topical skin disease applications. Since the off-rate of a covalently binding drug is negligible compared to that of a non-covalent drug, its therapeutic effects can be prolonged and typically, smaller doses of the drug are necessary to reach the same level of therapeutic efficacy, thereby potentially reducing systemic side effects. Different analogs of SEGRA GSK866 coupled to cysteine reactive warheads were characterized for GR potency and selectivity in various biochemical and cellular assays. GR- and NFκB-dependent reporter gene studies show favorable anti-inflammatory properties with reduced GR transactivation of two non-steroidal GSK866 analogs UAMC-1217 and UAMC-1218, whereas UAMC-1158 and UAMC-1159 compounds failed to modulate cellular GR activity. These results were further supported by GR immuno-localization and S211 phospho-GR western analysis, illustrating significant GR phosphoactivation and nuclear translocation upon treatment of GSK866, UAMC-1217, or UAMC-1218, but not in case of UAMC-1158 or UAMC-1159. Furthermore, mass spectrometry analysis of tryptic peptides of recombinant GR ligand-binding domain (LBD) bound to UAMC-1217 or UAMC-1218 confirmed covalent cysteine-dependent GR binding. Finally, molecular dynamics simulations, as well as glucocorticoid receptor ligand-binding domain (GR-LBD) coregulator interaction profiling of the GR-LBD bound to GSK866 or its covalently binding analogs UAMC-1217 or UAMC-1218 revealed subtle conformational differences that might underlie their SEGRA properties. Altogether, GSK866 analogs UAMC-1217 and UAMC-1218 hold promise as a novel class of covalent-binding SEGRA ligands for the treatment of topical inflammatory skin disorders.

The CEP genes play a pivotal role in the replication of the cell. CEP family proteins form the major constituents of the centrosome and play a prominent role in centriole biogenesis and in cell replication. Alteration in CEP genes will result in disruption of cell cycle that may in turn cause cancer. In our study, we found that 16 of the CEP genes are a potential target to miRNA that binds to complementary sequences in 3'untranslated regions (UTR) of mRNA and stop them from translation. Single nucleotide polymorphisms (SNPs) occurring naturally in such miRNA binding site can alter the miRNA: mRNA interaction and can significantly alter gene expression. We developed a systematic computational pipeline that integrates data from well-established databases, followed stringent selection criteria and identified a panel of 44 high-confidence SNPs that may impair miRNA target sites in the 3'UTR of 16 genes. Further we performed expression analysis to shed light on the potential tissues that might be affected by mutation, enrichment analysis to find the metabolic functions of the gene, and network analysis to highlight the important interactions of CEP genes with other genes to provide insight that complex network will be disturbed upon mutation. In this study, we explored and prioritised the SNPs in CEP gene which could act as a potential target in centrosome-associated human disease. Our analysis would provide a thoughtful insight to wet lab researches to understand the expression pattern of CEP genes and binding phenomenon of mRNA and miRNA upon mutation, which is responsible for inhibition of translation process at genomic levels.

Albinism is an autosomal recessive genetic disorder due to low secretion of melanin. The oculocutaneous albinism (OCA) and ocular albinism (OA) genes are responsible for melanin production and also act as a potential targets for miRNAs. The role of miRNA is to inhibit the protein synthesis partially or completely by binding with the 3'UTR of the mRNA thus regulating gene expression. In this analysis, we predicted the genetic variation that occurred in 3'UTR of the transcript which can be a reason for low melanin production thus causing albinism. The single nucleotide polymorphisms (SNPs) in 3'UTR cause more new binding sites for miRNA which binds with mRNA which leads to inhibit the translation process either partially or completely. The SNPs in the mRNA of OCA and OA genes can create new binding sites for miRNA which may control the gene expression and lead to hypopigmentation. We have developed a computational procedure to determine the SNPs in the 3'UTR region of mRNA of OCA (TYR, OCA2, TYRP1 and SLC45A2) and OA (GPR143) genes which will be a potential cause for albinism. We identified 37 SNPs in five genes that are predicted to create 87 new binding sites on mRNA, which may lead to abrogation of the translation process. Expression analysis confirms that these genes are highly expressed in skin and eye regions. It is well supported by enrichment analysis that these genes are mainly involved in eye pigmentation and melanin biosynthesis process. The network analysis also shows how the genes are interacting and expressing in a complex network. This insight provides clue to wet-lab researches to understand the expression pattern of OCA and OA genes and binding phenomenon of mRNA and miRNA upon mutation, which is responsible for inhibition of translation process at genomic levels.

Amyotrophic lateral sclerosis 6 (ALS6) is an autosomal recessive disorder caused by heterozygous mutation in the Fused in Sarcoma (FUS) gene. ALS6 is a neurodegenerative disorder, which affects the upper and lower motor neurons in the brain and spinal cord, resulting in fatal paralysis. ALS6 is caused by the genetic mutation in the proline/tyrosine-nuclear localization signals of the Fused in sarcoma Protein (FUS). FUS gene also known as TLS (Translocated in liposarcoma), which encodes a protein called RNA-binding protein-Fus (FUS), has a molecular weight of 75 kDa. In this analysis, we applied computational approach to filter the most deleterious and neurodegenerative disease of ALS6-associated mutation on FUS protein. We found H517Q as most deleterious and disease associated using PolyPhen 2.0, I-Mutant 3.0, SIFT, SNPsGO, PhD-SNP, Pmut, and Mutpred tools. Molecular dynamics simulation (MDS) approach was conducted to investigate conformational changes in the mutant protein structure with respect to its native conformation. MDS results showed the flexibility loss in mutant (H517Q) FUS protein. Due to mutation, FUS protein became more rigid in nature and might alter the structural and functional behavior of protein and play a major role in inducing ALS6. The results obtained from this investigation would help in the field of pharmacogenomics to develop a potent drug target against FUS-associated neurodegenerative diseases.

Fragrance in rice plays an important characteristic feature in determining the quality of rice. 2-Acetyl-1-pyrroline (2AP) compound is responsible for the fragrance in rice. Betaine-aldehyde-dehydr...

This study reports on the possible effects of OH radical impact on the transmembrane domain 6 of P-glycoprotein, TM6, which plays a crucial role in drug binding in human cells. For the first time, we employ molecular dynamics (MD) simulations based on the self-consistent charge density functional tight binding (SCC-DFTB) method to elucidate the potential sites of fragmentation and mutation in this domain upon impact of OH radicals and to obtain fundamental information about the underlying reaction mechanisms. Furthermore, we apply non-reactive MD simulations to investigate the long-term effect of this mutation, with possible implications for drug binding. Our simulations indicate that the interaction of OH radicals with TM6 might lead to the breaking of C-C and C-N peptide bonds, which eventually cause fragmentation of TM6. Moreover, according to our simulations, the OH radicals can yield mutation in the aromatic ring of phenylalanine in TM6, which in turn affects its structure. As TM6 plays an important role in the binding of a range of cytotoxic drugs with P-glycoprotein, any changes in its structure are likely to affect the response of the tumor cell in chemotherapy. This is crucial for cancer therapies based on reactive oxygen species, such as plasma treatment.

Oculocutaneous albinism type IV (OCA4) is an autosomal recessive inherited disorder which is characterized by reduced biosynthesis of melanin pigmentation in skin, hair, and eyes and caused by the genetic mutations in the membrane-associated transporter protein (MATP) encoded by SLC45A2 gene. The MATP protein consists of 530 amino acids which contains 12 putative transmembrane domains and plays an important role in pigmentation and probably functions as a membrane transporter in melanosomes. We scrutinized the most OCA4 disease-associated mutation and their structural consequences on SLC45A2 gene. To understand the atomic arrangement in 3D space, the native and mutant structures were modeled. Further the structural behavior of native and mutant MATP protein was investigated by molecular dynamics simulation (MDS) approach in explicit lipid and water background. We found Y317C as the most deleterious and disease-associated SNP on SLC45A2 gene. In MDS, mutations in MATP protein showed loss of stability and became more flexible, which alter its structural conformation and function. This phenomenon has indicated a significant role in inducing OCA4. Our study explored the understanding of molecular mechanism of MATP protein upon mutation at atomic level and further helps in the field of pharmacogenomics to develop a personalized medicine for OCA4 disorder. J. Cell. Biochem. 117: 2608-2619, 2016. © 2016 Wiley Periodicals, Inc.

Modelling at the molecular or atomic scale can be very useful for obtaining a better insight in plasma medicine. This paper gives an overview of different atomic/molecular scale modelling approaches that can be used to study the direct interaction of plasma species with biomolecules or the consequences of these interactions for the biomolecules on a somewhat longer time-scale. These approaches include density functional theory (DFT), density functional based tight binding (DFTB), classical reactive and non-reactive molecular dynamics (MD) and united-atom or coarse-grained MD, as well as hybrid quantum mechanics/molecular mechanics (QM/MM) methods. Specific examples will be given for three important types of biomolecules, present in human cells, i.e. proteins, DNA and phospholipids found in the cell membrane. The results show that each of these modelling approaches has its specific strengths and limitations, and is particularly useful for certain applications. A multi-level approach is therefore most suitable for obtaining a global picture of the plasma-biomolecule interactions.

Oculocutaneous albinism (OCA) is an autosomal recessive disorder caused by either complete lack of or a reduction of melanin biosynthesis in the melanocytes. The OCA1A is the most severe type with a complete lack of melanin production throughout life, while the milder forms OCA1B, OCA2, OCA3, and OCA4 show some pigment accumulation over time. Mutations in TYR, OCA2, TYRP1, and SLC45A2 are mainly responsible for causing oculocutaneous albinism. Recently, two new genes SLC24A5 and C10orf11 are identified that are responsible to cause OCA6 and OCA7, respectively. Also a locus has been mapped to the human chromosome 4q24 region which is responsible for genetic cause of OCA5. In this paper, we summarized the clinical and molecular features of OCA genes. Further, we reviewed the screening of pathological mutations of OCA genes and its molecular mechanism of the protein upon mutation byin silicoapproach. We also reviewed TYR (T373K, N371Y, M370T, and P313R), OCA2 (R305W), TYRP1 (R326H and R356Q) mutations and their structural consequences at molecular level. It is observed that the pathological genetic mutations and their structural and functional significance of OCA genes will aid in development of personalized medicine for albinism patients.

The Polo-like kinases (Plks) are a conserved subfamily of serine-threonine protein kinases that have significant roles in cell proliferation. The serine/threonine protein kinases or polo-like kinase 1 (PLK1) exist in centrosome during interphase and is an important regulatory enzyme in cell cycle progression during M phase. Mutations in mammalian PLK1 were found to be over expressed in various human cancers and it is disrupting the binding ability of polo box domain with target peptide. In this analysis we implemented a computational approach to filter the most deleterious and cancer associated mutation on PLK1 protein. We found W414F as the most deleterious and cancer associated by Polyphen 2.0, SIFT, I-mutant 3.0, PANTHER, PhD-SNP, SNP&GO, Mutpred and Dr Cancer tools. Molecular docking and molecular dynamics simulation (MDS) approach was used to investigate the structural and functional behavior of PLK1 protein upon mutation. MDS and docking results showed stability loss in mutant PLK1 protein. Due to mutation, PLK1 protein became more flexible and alters the dynamic property of protein which might affect the interaction with target peptide and leads to cell proliferation. Our study provided a well designed computational methodology to examine the cancer associated nsSNPs and their molecular mechanism. It further helps scientists to develop a drug therapy against PLK1 cancer-associated diseases.

BACKGROUND: Aurora kinases belong to the highly conserved kinase family and play a vital role in cell cycle regulation. The structure and function of these kinases are inter-related and sometimes they also act as substitutes in case of knockdown of other aurora kinases. METHOD: In this work we carried out the evolutionary reconstruction and population genetic studies of aurora kinase proteins. Substitution saturation test, CAI (Codon adaptation index), gene expression and RSCU (Relative synonymous codon usage) values were computed for all the three aurora kinases. Linear regression method was used to check the dependency of gene expression on their CAI values. RESULTS: The results suggested that aurora-B and aurora-C has shown convergence in their evolutionary pathway. Moreover, the aurora-A I57V mutation showed high penetrance in human population and exist at very high frequency (84.4%) when compared to the native residue (15.6%). The mutation showed notable range of functional gain and seemed to be promising for the evolution of aurora-A function. Mutant allele might also become a challenging prospect for understanding the pattern of evolution followed by cell cycle kinases. CONCLUSION: The overall result suggested that the aurora-A is currently under the evolutionary transition and to determine the functional significance of the mutation further investigation are required.

Oculocutaneous albinism type III (OCA3), caused by mutations of TYRP1 gene, is an autosomal recessive disorder characterized by reduced biosynthesis of melanin pigment in the hair, skin, and eyes. The TYRP1 gene encodes a protein called tyrosinase-related protein-1 (Tyrp1). Tyrp1 is involved in maintaining the stability of tyrosinase protein and modulating its catalytic activity in eumelanin synthesis. Tyrp1 is also involved in maintenance of melanosome structure and affects melanocyte proliferation and cell death. In this work we implemented computational analysis to filter the most probable mutation that might be associated with OCA3. We found R326H and R356Q as most deleterious and disease associated by using PolyPhen 2.0, SIFT, PANTHER, I-mutant 3.0, PhD-SNP, SNP&GO, Pmut, and Mutpred tools. To understand the atomic arrangement in 3D space, the native and mutant (R326H and R356Q) structures were modelled. Finally the structural analyses of native and mutant Tyrp1 proteins were investigated using molecular dynamics simulation (MDS) approach. MDS results showed more flexibility in native Tyrp1 structure. Due to mutation in Tyrp1 protein, it became more rigid and might disturb the structural conformation and catalytic function of the structure and might also play a significant role in inducing OCA3. The results obtained from this study would facilitate wet-lab researches to develop a potent drug therapies against OCA3.

Genetic evolution corresponds to various biochemical changes that are vital development of new functional traits. Phylogenetic analysis has provided an important insight into the genetic closeness among species and their evolutionary relationships. Centromere-associated protein-E (CENP-E) protein is vital for maintaining cell cycle and checkpoint signal mechanisms are vital for recruitment process of other essential kinetochore proteins. In this study we have focussed on the evolution driven structural changes in CENP-E motor domain among primate lineage. Through molecular dynamics simulation and computational chemistry approaches we examined the changes in ATP binding affinity and conformational deviations in human CENP-E motor domain as compared to the other primates. Root mean square deviation (RMSD), Root mean square fluctuation (RMSF), Radius of gyration (Rg) and principle component analysis (PCA) results together suggested a gain in stability level as we move from tarsier towards human. This study provides a significant insight into how the cell cycle proteins and their corresponding biochemical activities are evolving and illustrates the potency of a theoretical approach for assessing, in a single study, the structural, functional, and dynamical aspects of protein evolution.