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Background: Thrombotic disease is still a major killer. Aspirin, Ticagrelor, Clopidogrel, etc. are the most widely used conventional antiplatelet drugs. The significant number of patients who are resistant to this drug shows a poor outcome. Objective: Developing a new antiplatelet agent with a stable antiplatelet effect and minimal bleeding risk is required for a patient who is resistant to antiplatelet drugs. Method: Protein-ligand docking was performed using Autodock Vina 1.1.2 to study the interaction of 67LR with different Polyphenols. Result: Among the 18 polyphenols, thearubigin has the highest binding affinity towards 67LR and gallic acid shows the lowest binding affinity. Among the 18 molecules, the top 10 molecules from the highest to lowest binding affinity range from-10.6 (thearubigin) to -6.5 (Epigallocatechin). Conclusion: Polyphenols may inhibit platelet aggregation through 67 LR and can be an alternative treatment for Thrombotic Disease. Moreover, it will be interesting to know whether polyphenols interfere with the same pathways as aspirin and clopidogrel. Effective polyphenols could help prototype the compound development of novel antiplatelet agents.

COVID-19 is a sneaking deadly disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The rapid increase in the number of infected patients worldwide enhances the exigency for medicines. However, precise therapeutic drugs are not available for COVID-19; thus, exhaustive research is critically required to unscramble the pathogenic tools and probable therapeutic targets for the development of effective therapy. This study utilizes a chemogenomics strategy, including computational tools for the identification of viral-associated differentially expressed genes (DEGs), and molecular docking of potential chemical compounds available in antiviral, anticancer, and natural product-based libraries against these DEGs. We scrutinized the messenger RNA expression profile of SARS-CoV-2 patients, publicly available on the National Center for Biotechnology Information-Gene Expression Omnibus database, stratified them into different groups based on the severity of infection, superseded by identification of overlapping mild and severe infectious (MSI)-DEGs. The profoundly expressed MSI-DEGs were then subjected to trait-linked weighted co-expression network construction and hub module detection. The hub module MSI-DEGs were then exposed to enrichment (gene ontology + pathway) and protein-protein interaction network analyses where Rho guanine nucleotide exchange factor 1 (ARHGEF1) gene conjectured in all groups and could be a probable target of therapy. Finally, we used the molecular docking and molecular dynamics method to identify inherent hits against the ARHGEF1 gene from antiviral, anticancer, and natural product-based libraries. Although the study has an identified significant association of the ARHGEF1 gene in COVID19; and probable compounds targeting it, using in silico methods, these targets need to be validated by both in vitro and in vivo methods to effectively determine their therapeutic efficacy against the devastating virus.

What do scraps of bones discovered in a deserted Siberian Cave in Russia have to do with us? Or how do a few fragments of teeth in Gibraltar, an isolated British overseas territory located at the southern tip of the Iberian Peninsula, have to do with the genetic legacy of today’s living people across Asia? Well, it seems that about 40,000 years back, we humans were not the only inhabiting hominids on this planet Earth; we had other mysterious cousins, at least two of them known so far, who had left enough evidence and trails of DNA for the scientist to ponder. Like crime cases that run cold due to lack of solid evidence, paleontologists often tumble when encountering roadblocks; until Swedish Geneticists Svante Pääbo painstakingly developed the necessary tools and techniques to trace back our origin, 15000 years back when perhaps the three hominids even crisscrossed each other’s path. The Desonovians, the Nearthandals, and the modern-day humans. The two ancestors of humans perhaps arose from a common origin several thousand years back. We now know that the Desinovinans diverged from their close relatives, the Neanderthals, around 400,000 years ago, while they both diverged from modern Homo sapiens around 800,000 years ago. The Neanderthals were populated in Europe and Asia, while the more elusive Desonovians were restricted to Siberia, in regions of eastern and southern Eurasia. Genomic homology studies revealed that the Denisova’s mitochondrial DNA differs from that of modern humans by 385 bases, whereas the difference with Neanderthals is around 202 bases. These numbers stand out from the difference between chimpanzees and modern humans, approximately 1462 base pairs. It is now conclusively known that sometimes in prehistoric times, there had been an event of DNA mixing between the Denisovans and modern humans, an event of actual sexual mating. The percentage of Denisovan DNA is highest in the Melanesian population (Melanesians are the indigenous inhabitants of Melanesia, from New Guinea to the Fiji Islands), lower in other Southeast Asian and Pacific Islander populations, with hardly any DNA detectable in other populations in the world. What is enigmatic is how this human cousin got extinct. Possibly a competition for resources was likely one reason the Denisovans went extinct. The evolutionary trajectory of the Nearthandals followed a different route. At least, two different groups of Neanderthals who lived in Southern Siberia seem to have migrated from Eastern Europe. Not only that, just that Denisovans also interbred with modern-day humans. This interesting phenomenon is called Introgression. It explains why modern-day humans have some Neanderthal DNA, roughly about 3%. Human ancestors only lived in Africa until they decided to migrate to Europe some 45,000 years ago. It’s there where they encountered its other ancestors, the Neanderthals (Homo neanderthalensis). Eventually, they mated and produced offspring resulting in Introgression. Since this mating event happened outside Africa, present-day African people have no traces of Neanderthal DNA. However, due to interesting adaptive advantages, modern-day humans (outside Africa) still retained 3% of Neanderthal DNA, a spectacular observation even 40,000 years after they might have last mated. This is called adaptive Introgression. This is also where Darwin’s principles of natural selection come in. Retaining the 3% Neanderthals might serve some advantage to Modern Humans for better adaptations, something that the sickle mutated DNA at one allele (heterozygous) got positively adapted in Africa due to its protective effect against the malarial parasite in malariaendemic areas. Things can get even interesting and weird with the findings that hybrid individuals were discovered who carried both the Denisovan as well as Neanderthal DNA. That’s what the team, led by palaeogeneticists Slon et al., reported in Nature. Named as “Denny,” thischild seems to be born from a Neanderthal mother and a Desinovan dad, some 90,000 years back. Denny seems to be born out of mating of two extinct hominid ancestors, acquiring one set of chromosomes from a Neanderthal and the other from a Denisovan. Shaped by evolution and driven by its migratory nature, present-day human is the cumulative outcome of thousands of years of man’s struggle for its survival. Driven by the changing environmental its migration journey picked with it traces of DNA from its ancestral cousins that it encountered. Meticulous investigation of this apparently insignificant DNA holds the secret of thousands of years of human history and human migration. Relentless efforts by Prof Svante Pääbo and other researchers have shed light on our ancestral autobiography.

Nature and nurture have always been a prerogative of evolutionary biologists. The environment’s role in shaping an organism’s phenotype has always intrigued us. Since the inception of humankind, twinning has existed with an unsettled parley on the contribution of nature (i.e. genetics) versus nurture (i.e. environment), which can influence the phenotypes. The study of twins measures the genetic contribution and that of the environmental influence for a particular trait, acting as a catalyst, fine-tuning the phenotypic trajectories. This is further evident because a number of human diseases show a spectrum of clinical manifestations with the same underlying molecular aberration. As of now, there is no definite way to conclude just from the genomic data the severity of a disease or even to predict who will get affected. This greatly justifies initiating a twin registry for a country as diverse and populated as India. There is an unmet need to set up a nationwide database to carefully curate the information on twins, serving as a valuable biorepository to study their overall susceptibility to disease. Establishing a twin registry is of paramount importance to harness the wealth of human information related to the biomedical, anthropological, cultural, social and economic significance.

Alkaptonuria (AKU) is an autosomal recessive disorder, which is caused by a site-specific mutation(s) and thus, impaired the function of Homogentisate-1, 2-dioxygenase (HGD), an essential enzyme for the catabolism of phenylalanine and tyrosine. Among frameshift, intronic, splice-site and missense mutations, the latter has been the most common form of genetic variations for the disease. How do the acquired mutations in HGD correlate with the disease? Systematic staged-screening of some sixty-five mutations, which are known to have a relation with the disease, by GVGD, SIFT, SNAP, PANTHER, SDM, PHD-SNP, Meta-SNP, Pmut and Mutpred methods, showed that mutations

Paromomycin, an aminoglycoside antibiotic, is an effective treatment for VL (visceral leishmaniasis) in India. The modification of aminoglycoside antibiotics by enzymes such as aminoglycoside acetyltransferases is the predominant mechanism of resistance to antibiotics in bacterial system. In the present study, we identified and characterized LdATLP (an acetyltransferase-like protein) and elucidated its role in paromomycin resistance in Leishmania donovani. Gene encoding LdATLP was consistently up-regulated (>2fold) in three distinct paromomycin resistant in comparison with sensitive parasites, although the gene sequence was identical in the two. In silico analysis revealed that LdATLP consisted of conserved GNAT (GCN5-related N-Acetyltransferase) domain which is characteristic of aminoglycoside N-acetyltransferases. Evolutionary relationship among LdATLP of Leishmania and aminoglycoside acetyltransferases of bacteria was established by phylogenetic analysis. The 3D structure of LdATLP, predicted by ab-initio modeling, constituted 6 α-helices and 6 β-sheets. A few residues, such as R175, R177, E196, R197, V198, V200, K202, R205, C206, D208, G210, R211, R215, A234, S237, S238, K239, D240, F241 and Y242 of GNAT domain were predicted to be present at active site. Molecular docking of LdATLP with paromomycin or indolicidin (broad spectrum inhibitor of aminoglycoside modifying enzymes), followed by molecular dynamics simulation of docked complex suggested that both paromomycin and indolicidin bind to LdATLP with comparable free energy of binding. In vitro studies revealed that in the presence of indolicidin, paromomycin resistant parasites exhibited reversion of phenotype into sensitive parasites with marked increase in paromomycin susceptibility, suggesting the role of LdATLP in paromomycin resistance.Communicated by Ramaswamy H. Sarma.

The emergence of multidrug-resistant strains of Candida albicans has become a global threat mostly due to co-infection with immune-compromised patients leading to invasive candidiasis. The life-threatening form of the disease can be managed quickly and effectively by drug repurposing. Thus, the study used in silico approaches to evaluate Food and Drug Administration (FDA) approved drugs against three drug targets-TRR1, TOM40, and YHB1. The tertiary structures of three drug targets were modeled, refined, and evaluated for their structural integrity based on PROCHECK, ERRAT, and PROSA. High-throughput virtual screening of FDA-approved drugs (8815), interaction analysis, and energy profiles had revealed that DB01102 (Arbutamine), DB01611 (Hydroxychloroquine), and DB09319 (Carindacillin) exhibited better binding affinity with TRR1, TOM40, and YHB1, respectively. Notably, the molecular dynamic simulation explored that Gln45, Thr119, and Asp288 of TRR1; Thr107 and Ser121 of TOM40; Arg193, Glu213, and Ser228 of YHB1 are crucial residues for stable drug-target interaction. Additionally, it also prioritized Arbutamine-TRR1 as the best drug-target complex based on MM-PBSA (-52.72 kcal/mol), RMSD (2.43 A), and radius of gyration (-21.49 A) analysis. In-depth, PCA results supported the findings of molecular dynamic simulations. Interestingly, the conserved region (>70%) among the TRR1 sequences from pathogenic Candida species indicated the effectiveness of Arbutamine against multiple species of Candida as well. Thus, the study dispenses new insight and enriches the understanding of developing an advanced technique to consider potential antifungals against C. albicans. Nonetheless, a detailed experimental validation is needed to investigate the efficacy of Arbutamin against life-threatening candidiasis.

The scaffold structure of noscapine (an antitussive plant alkaloid) was modified by inducting N-aryl methyl pharmacophore at C-9 position of the isoquinoline ring to rationally design and screened three novel 9-(N-arylmethylamino) noscapinoids, 15-17 with robust binding affinity with tubulin. The selected 9-(N-arylmethylamino) noscapinoids revealed improved predicted binding energy of -6.694 kcal/mol for 15, -7.118 kcal/mol for 16 and -7.732 kcal/mol for 17, respectively in comparison to the lead molecule (-5.135 kcal/mol). These novel derivatives were chemically synthesized and validated their anticancer activity based on cellular studies using two human breast adenocarcinoma, MCF-7 and MDA-MB-231, as well as with a panel of primary breast tumor cells. These derivatives inhibited cellular proliferation in all the cancer cells that ranged between 3.2 and 32.2 μM, which is 11.9 to 1.8 fold lower than that of noscapine. These novel derivatives effectively arrest the cell cycle in the G2/M phase followed by apoptosis and appearance of apoptotic cells. Thus, we conclude that 9-(N-arylmethyl amino) noscapinoids, 15-17 have a high probability to be a novel therapeutic agent for breast cancers.

Alkaptonuria (AKU) is an autosomal recessive disorder, which is caused by a site-specific mutation(s) and thus, impaired the function of Homogentisate-1, 2-dioxygenase (HGD), an essential enzyme for the catabolism of phenylalanine and tyrosine. Among frameshift, intronic, splice-site and missense mutations, the latter has been the most common form of genetic variations for the disease. How do the acquired mutations in HGD correlate with the disease? Systematic staged-screening of some sixty-five mutations, which are known to have a relation with the disease, by GVGD, SIFT, SNAP, PANTHER, SDM, PHD-SNP, Meta-SNP, Pmut and Mutpred methods, showed that mutations, W60G, A122D and V300G are potentially related with the severity of AKU. Detailed analyses on molecular docking and molecular dynamics simulation (MDS) of these mutants against the wild-type HGD reveal the loss of structural and molecular dynamic properties of the enzyme. Further, the observed conformational flexibility in mutants at targeted peptide segments seems to have a relation with the impairment of the function of HGD. Taken together, the study involves a designed computational methodology to analyse the disease-associated nsSNPs for AKU, the knowledge of which seems to have potential applications in drug therapies for the disease in particular and other similar systems in general. Communicated by Ramaswamy H. Sarma

Wealth of structural data on theurapeutic targets in complex with monoclonal antibodies (mAbs) and advances in molecular modeling algorithms present exciting opportunities in the field of novel biologic design. Interleukin 23 (IL23), a well-known drug target for autoimmune diseases, in complex with mAb 7G10 offers prospect to design potent lead antibodies by traversing the complete epitope-paratope interface. Herein, key interactions aiding antibody-based neutralization in IL23-7G10 complex are resolute through PyMOL, LigPlot

Psoriasis is a systemic hyperproliferative inflammatory skin disorder, although rarely fatal but significantly reduces quality of life. Understanding the full genetic component of the disease association may provide insight into biological pathways as well as targets and biomarkers for diagnosis, prognosis and therapy. Studies related to psoriasis associated genes and genetic markers are scattered and not easily amendable to data-mining. To alleviate difficulties, we have developed dbGAPs an integrated knowledgebase representing a gateway to psoriasis associated genomic data. The database contains annotation for 202 manually curated genes associated with psoriasis and its subtypes with cross-references. Functional enrichment of these genes, in context of Gene Ontology and pathways, provide insight into their important role in psoriasis etiology and pathogenesis. The dbGAPs interface is enriched with an interactive search engine for data retrieval along with unique customized tools for Single Nucleotide Polymorphism (SNP)/indel detection and SNP/indel annotations. dbGAPs is accessible at http://www.bmicnip.in/dbgaps/ .

Computer-aided antibody engineering has been successful in the design of new biologics for disease diagnosis and therapeutic interventions. Interleukin-6 (IL-6), a well-recognized drug target for various autoimmune and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, and psoriasis, was investigated in silico to design potential lead antibodies. Here, crystal structure of IL-6 along with monoclonal antibody olokizumab was explored to predict antigen-antibody (Ag - Ab)-interacting residues using DiscoTope, Paratome, and PyMOL. Tyr56, Tyr103 in heavy chain and Gly30, Ile31 in light chain of olokizumab were mutated with residues Ser, Thr, Tyr, Trp, and Phe. A set of 899 mutant macromolecules were designed, and binding affinity of these macromolecules to IL-6 was evaluated through Ag - Ab docking (ZDOCK, ClusPro, and Rosetta server), binding free-energy calculations using Molecular Mechanics/Poisson Boltzman Surface Area (MM/PBSA) method, and interaction energy estimation. In comparison to olokizumab, eight newly designed theoretical antibodies demonstrated better result in all assessments. Therefore, these newly designed macromolecules were proposed as potential lead antibodies to serve as a therapeutics option for IL-6-mediated diseases.

Psoriasis is an immune mediated inflammatory skin disease with complex etiology involving interplay between environmental and genetic risk factors as disease initiating event. Enhanced understanding on genetic risk factors, differentially expressed genes, deregulated proteins and pathway-targeted therapeutics have established multiple axis of psoriasis pathogenesis. So far, loci in 424 genes are reported to be associated with psoriasis alongside copy number variations and epigenetic alterations. From clinical perspective, presence of specific genetic trigger(s) in individual psoriasis patient could aid in devising a personalized therapeutic strategy. Therefore, the review presents an updates on reported genomic alterations and their subsequent course of cutaneous inflammations that potentially drive to psoriasis.

Specific electrostatics (i.e. salt-bridge) includes both local and non-local interactions that contribute to the overall stability of proteins. It has been shown that a salt-bridge could either be buried or exposed, networked or isolated, hydrogen-bonded or nonhydrogen bonded, in secondary-structure or in coil, formed by single or multiple bonds. Further it could also participates either in intra- or inter-dipole interactions with preference in orientation either for basic residue at N-terminal (orientation-I) or acidic residue at N-terminal (orientation-II). In this context SBION2 is unique in that it reports above mentioned binary items in excel format along with details on intra and inter-dipole interactions and orientations. These results are suitable for post run statistical analyses involving large datasets. Reports are also made on protein-protein interactions, intervening residue distances and general residue specific salt-bridge details. A ready to use compact supplementary table is also produced. The program runs in three alternative modes. Each mode works on any number of structure files with any number of chains at any given atomic distance of ion-pair. Thus SBION2 provides intricate details on salt-bridges and finds application in structural bioinformatics. Availability SBION2 is freely available at http://sourceforge.net/projects/sbion2/ for academic users

Component (bridge: ΔΔGbrd, background: ΔΔGprot, desolvation: ΔΔGdsolv) and net (ΔΔGnet) energy-terms of salt-bridge-structure (SBS) are auto-generated by the program ADSBET that makes use of general purpose Adaptive Poison Boltzmann Solver (APBS) method. While the procedure reports gross energy terms (Kcal Mol-1), report on bond-multiplicity corrected normalized energyterms (Kcal Mol-1 Bond-1) along with their accessibility (ASA) in monomer, isolated-SBS (ISBS) and networked-SBS (NSBS) format would be very useful for statistical comparison among SBSs and understanding their location in protein structure. In this end, ADSBET2 potentially incorporates these features along with additional model for side-chain. Gross and normalized energy-terms are redirected in monomer, ISBS and NSBS format along with their ASA informations. It works on any number of SBSs for any number of structure files present in a database. Taken together, ADSBET2 has been suitable for statistical analyses of SBSs energetics and finds applications in protein engineering and structural bioinformatics. Availability ADSBET2 is freely available at http://sourceforge.net/projects/ADSBET2/ for all users.

Automated genome sequencing procedure is enriching the sequence database very fast. To achieve a balance between the entry of sequences in the database and their analyses, efficient software is required. In this end PHYSICO2, compare to earlier PHYSICO and other public domain tools, is most efficient in that it i] extracts physicochemical, window-dependent and homologousposition-based-substitution (PWS) properties including positional and BLOCK-specific diversity and conservation, ii] provides users with optional-flexibility in setting relevant input-parameters, iii] helps users to prepare BLOCK-FASTA-file by the use of Automated Block Preparation Tool of the program, iv] performs fast, accurate and user-friendly analyses and v] redirects itemized outputs in excel format along with detailed methodology. The program package contains documentation describing application of methods. Overall the program acts as efficient PWS-analyzer and finds application in sequence-bioinformatics. Availability PHYSICO2: is freely available at http://sourceforge.net/projects/physico2/ along with its documentation at https://sourceforge.net/projects/physico2/files/Documentation.pdf/download for all users.

Bone marrow kinase in the X chromosome (BMX), a Tec family kinase, play important role in monocyte ⁄macrophage function and trafficking. BMX is expressed in bone marrow, granulo ⁄monocytic cells an...

Halophilic proteins have greater abundance of acidic over basic and very low bulky hydrophobic residues. Classical electrostatic stabilization was suggested as the key determinant for halophilic adaptation of protein. However, contribution of specific electrostatic interactions (i.e. salt-bridges) to overall stability of halophilic proteins is yet to be understood. To understand this, we use Adaptive-Poison-Boltzmann-Solver Methods along with our home-built automation to workout net as well as associated component energy terms such as desolvation energy, bridge energy and background energy for 275 salt-bridges from 20 extremely halophilic proteins. We then perform extensive statistical analysis on general and energetic attributes on these salt-bridges. On average, 8 salt-bridges per 150 residues protein were observed which is almost twice than earlier report. Overall contributions of salt-bridges are -3.0 kcal mol-1. Majority (78%) of salt-bridges in our dataset are stable and conserved in nature. Although, average contributions of component energy terms are equal, their individual details vary greatly from one another indicating their sensitivity to local micro-environment. Notably, 35% of salt-bridges in our database are buried and stable. Greater desolvation penalty of these buried salt-bridges are counteracted by stable network salt-bridges apart from favorable equal contributions of bridge and background terms. Recruitment of extensive network salt-bridges (46%) with a net contribution of -5.0 kcal mol-1 per salt-bridge, seems to be a halophilic design wherein favorable average contribution of background term (-10 kcal mol-1) exceeds than that of bridge term (-7 kcal mol-1). Interiors of proteins from halophiles are seen to possess relatively higher abundance of charge and polar side chains than that of mesophiles which seems to be satisfied by cooperative network salt-bridges. Overall, our theoretical analyses provide insight into halophilic signature in its specific electrostatic interactions which we hope would help in protein engineering and bioinformatics studies.