cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.15180297.v1
title: Deciphering the structural and functional impact of missense mutations in Egr1-DNA interacting interface: an integrative computational approach

description: Early growth response-1 (Egr1) is a zinc-finger transcription factor that plays a critical role in controlling cell growth, proliferation, differentiation, angiogenesis, and apoptosis. Egr1 is induced by many growth factors, cytokines, and stress signals and is also known to be involved in several pathological conditions like cancer, neurological and ocular disorders. The DNA binding domain of Egr1 is a highly conserved Cys2His2 (C2H2) zinc finger (ZNF) domain which specifically binds to GC-rich consensus sequence GcG (G/T) GGGCG and activates transcription. As the C2H2 domain specifically recognizes its DNA target, the mutations spanning this region shall perturb DNA recognition and may hinder transcription of target genes. Therefore, in this study, the missense mutations occurring specifically at the DNA binding domain (DBD) of Egr1 were probed by computational approaches involving <i>in silico</i> screening of pathogenic and functional mutants coupled with extensive molecular dynamics simulations, to determine the mutants that affect its structural stability and interactions with DNA. From the pathogenicity analysis of 38 missense mutations spanning Egr1-DBD, 17 were predicted as pathogenic, and 7 amongst these were found to have functional impact on Egr1. On combined analysis of molecular dynamics simulation, Residue interaction analysis and Egr1<i>-</i>DNA interaction analysis results, the mutants R371C and R375C showed least impact, whilst, H382R tend to increase the structural stability, whereas R360H, H390R, E393V, and H414Y conferred greater impact by altering the structural stability and DNA interactions. Hence, this study exposes the prospects of considering these 4 deleterious mutations for clinical significance, but needs further experimental validation.Highlights<i>Egr1’s</i> DNA binding domain is a highly conserved Cys2His2 (C2H2) zinc finger domain that specifically recognizes its DNA target.Mutations spanning in the DNA binding domain shall perturb DNA recognition and may hinder transcription.Among the missense mutations, mutants R360H, H390R, E393V, and H414Y were inferred to have a greater impact on <i>Egr1</i> by altering the structural stability and DNA interactions. <i>Egr1’s</i> DNA binding domain is a highly conserved Cys2His2 (C2H2) zinc finger domain that specifically recognizes its DNA target. Mutations spanning in the DNA binding domain shall perturb DNA recognition and may hinder transcription. Among the missense mutations, mutants R360H, H390R, E393V, and H414Y were inferred to have a greater impact on <i>Egr1</i> by altering the structural stability and DNA interactions.
DOI: 10.6084/m9.figshare.16421649
title: In silico study on spice-derived antiviral phytochemicals against SARS-CoV-2 TMPRSS2 target

description: Corona Virus Disease (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a pandemic that has claimed so far over half a million human life across the globe. Researchers all over the world are exploring various molecules including phytochemicals to get a potential anti-COVID-19 drug. Certain phytochemicals present in some spices are claimed to possess antiviral, anti-bacterial, and anti-fungal properties. Hence, an <i>in-silico</i> study was done by selecting eighteen well reported antiviral phytochemicals from some spices commonly used in Indian kitchen viz. <i>Curcuma longa</i> (Turmeric), <i>Nigella sativa</i> (Black cumin), <i>Piper nigrum</i> (Black pepper), <i>Trachyspermum ammi</i> (Carom) and <i>Zingiber officinale</i> (Ginger) to find out whether they can prevent SARS-CoV-2 infection. Firstly, we predicted the structure of TMPRSS2 (transmembrane protease serine 2), a host protein that truncates spike protein of SARS-CoV-2 thereby facilitating its endocytosis, and then docked against its catalytic domain the selected phytochemicals and camostat (a well-known synthetic inhibitor of TMPRSS2). Thereafter, stability of seven best docked phytochemicals and camostat were scrutinized by Molecular Dynamic Simulation (MDS). MDS analysis indicated bisdemethoxycurcumin (BDMC), carvacrol and thymol as better inhibitors than the camostat due to their stable binding with TMPRSS2 in its oxyanion hole and inducing subtle modification in the spatial arrangement of the catalytic triad residues. Among these three phytochemicals, carvacrol appeared to be the best inhibitor, followed by BDMC, whereas thymol was least effective. HighlightsTMPRSS2 facilitate the entry of SARS-CoV-2 in the host cellSpices have numerous potent anti-viral phytochemicalsThe study identified the phytochemicals (BDMC, carvacrol and thymol) as potent inhibitor candidates of TMPRSS2 TMPRSS2 facilitate the entry of SARS-CoV-2 in the host cell Spices have numerous potent anti-viral phytochemicals The study identified the phytochemicals (BDMC, carvacrol and thymol) as potent inhibitor candidates of TMPRSS2 Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.16421649.v1
title: In silico study on spice-derived antiviral phytochemicals against SARS-CoV-2 TMPRSS2 target

description: Corona Virus Disease (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a pandemic that has claimed so far over half a million human life across the globe. Researchers all over the world are exploring various molecules including phytochemicals to get a potential anti-COVID-19 drug. Certain phytochemicals present in some spices are claimed to possess antiviral, anti-bacterial, and anti-fungal properties. Hence, an <i>in-silico</i> study was done by selecting eighteen well reported antiviral phytochemicals from some spices commonly used in Indian kitchen viz. <i>Curcuma longa</i> (Turmeric), <i>Nigella sativa</i> (Black cumin), <i>Piper nigrum</i> (Black pepper), <i>Trachyspermum ammi</i> (Carom) and <i>Zingiber officinale</i> (Ginger) to find out whether they can prevent SARS-CoV-2 infection. Firstly, we predicted the structure of TMPRSS2 (transmembrane protease serine 2), a host protein that truncates spike protein of SARS-CoV-2 thereby facilitating its endocytosis, and then docked against its catalytic domain the selected phytochemicals and camostat (a well-known synthetic inhibitor of TMPRSS2). Thereafter, stability of seven best docked phytochemicals and camostat were scrutinized by Molecular Dynamic Simulation (MDS). MDS analysis indicated bisdemethoxycurcumin (BDMC), carvacrol and thymol as better inhibitors than the camostat due to their stable binding with TMPRSS2 in its oxyanion hole and inducing subtle modification in the spatial arrangement of the catalytic triad residues. Among these three phytochemicals, carvacrol appeared to be the best inhibitor, followed by BDMC, whereas thymol was least effective. HighlightsTMPRSS2 facilitate the entry of SARS-CoV-2 in the host cellSpices have numerous potent anti-viral phytochemicalsThe study identified the phytochemicals (BDMC, carvacrol and thymol) as potent inhibitor candidates of TMPRSS2 TMPRSS2 facilitate the entry of SARS-CoV-2 in the host cell Spices have numerous potent anti-viral phytochemicals The study identified the phytochemicals (BDMC, carvacrol and thymol) as potent inhibitor candidates of TMPRSS2 Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.16411216
title: Venetoclax: a promising repurposed drug against SARS-CoV-2 main protease

description: Global health care emergency caused by a new coronavirus (severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2) demands urgent need to repurpose the approved pharmaceutical drugs. Main protease, M<sup>pro</sup> of SARS-CoV-2 draws significant attention as a drug target. Herein, we have screened FDA approved organosulfur drugs (till 2016) and our laboratory synthesized organosulfur and organoselenium compounds (L1-L306) against M<sup>pro</sup>-apo using docking followed by classical MD simulations. Additionally, a series of compounds (L307-L364) were chosen from previous experimental studies, which were reported to exhibit inhibitory potentials towards M<sup>pro</sup>. We found several organosulfur drugs, particularly Venetoclax (FDA approved organosulfur drug for Leukemia) to be a high-affinity binders to the M<sup>pro</sup> of SARS-CoV-2. The results reveal that organosulfur compounds including Venetoclax preferentially bind (non-covalently) to the non-catalytic pocket of the protein located in the dimer interface. We found that the ligand binding is primarily favoured by ligand-protein van der Waals interaction and penalized by desolvation effect. Interestingly, Venetoclax binding alters the local flexibility of M<sup>pro</sup> and exerts pronounced effect in the C-terminal as well as two loop regions (Loop-A and Loop-B) that play important roles in catalysis. These findings highlighted the importance of drug repurposing and explored the non-catalytic pockets of M<sup>pro</sup> in combating COVID-19 infection in addition to the importance of catalytic binding pocket of the protein. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.16411216.v2
title: Venetoclax: a promising repurposed drug against SARS-CoV-2 main protease

description: Global health care emergency caused by a new coronavirus (severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2) demands urgent need to repurpose the approved pharmaceutical drugs. Main protease, M<sup>pro</sup> of SARS-CoV-2 draws significant attention as a drug target. Herein, we have screened FDA approved organosulfur drugs (till 2016) and our laboratory synthesized organosulfur and organoselenium compounds (L1-L306) against M<sup>pro</sup>-apo using docking followed by classical MD simulations. Additionally, a series of compounds (L307-L364) were chosen from previous experimental studies, which were reported to exhibit inhibitory potentials towards M<sup>pro</sup>. We found several organosulfur drugs, particularly Venetoclax (FDA approved organosulfur drug for Leukemia) to be a high-affinity binders to the M<sup>pro</sup> of SARS-CoV-2. The results reveal that organosulfur compounds including Venetoclax preferentially bind (non-covalently) to the non-catalytic pocket of the protein located in the dimer interface. We found that the ligand binding is primarily favoured by ligand-protein van der Waals interaction and penalized by desolvation effect. Interestingly, Venetoclax binding alters the local flexibility of M<sup>pro</sup> and exerts pronounced effect in the C-terminal as well as two loop regions (Loop-A and Loop-B) that play important roles in catalysis. These findings highlighted the importance of drug repurposing and explored the non-catalytic pockets of M<sup>pro</sup> in combating COVID-19 infection in addition to the importance of catalytic binding pocket of the protein. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.16411216.v1
title: Venetoclax: a promising repurposed drug against SARS-CoV-2 main protease

description: Global health care emergency caused by a new coronavirus (severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2) demands urgent need to repurpose the approved pharmaceutical drugs. Main protease, M<sup>pro</sup> of SARS-CoV-2 draws significant attention as a drug target. Herein, we have screened FDA approved organosulfur drugs (till 2016) and our laboratory synthesized organosulfur and organoselenium compounds (L1-L306) against M<sup>pro</sup>-apo using docking followed by classical MD simulations. Additionally, a series of compounds (L307-L364) were chosen from previous experimental studies, which were reported to exhibit inhibitory potentials towards M<sup>pro</sup>. We found several organosulfur drugs, particularly Venetoclax (FDA approved organosulfur drug for Leukemia) to be a high-affinity binders to the M<sup>pro</sup> of SARS-CoV-2. The results reveal that organosulfur compounds including Venetoclax preferentially bind (non-covalently) to the non-catalytic pocket of the protein located in the dimer interface. We found that the ligand binding is primarily favoured by ligand-protein van der Waals interaction and penalized by desolvation effect. Interestingly, Venetoclax binding alters the local flexibility of M<sup>pro</sup> and exerts pronounced effect in the C-terminal as well as two loop regions (Loop-A and Loop-B) that play important roles in catalysis. These findings highlighted the importance of drug repurposing and explored the non-catalytic pockets of M<sup>pro</sup> in combating COVID-19 infection in addition to the importance of catalytic binding pocket of the protein. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.16574346
title: <i>In silico</i> prediction of natural compounds as potential multi-target inhibitors of structural proteins of SARS-CoV-2

description: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a colossal loss to human health and lives and has deeply impacted socio-economic growth. Remarkable efforts have been made by the scientific community in containing the virus by successful development of vaccines and diagnostic kits. Initiatives towards drug repurposing and discovery have also been undertaken. In this study, we compiled the known natural anti-viral compounds using text mining of the literature and examined them against four major structural proteins of SARS-CoV-2, namely, spike (S) protein, nucleocapsid (N) protein, membrane (M) protein and envelope (E) protein. Following computational approaches, we identified fangchinoline and versicolactone C as the compounds to exhibit strong binding to the target proteins and causing structural deformation of three structural proteins (N, S and M). We recommend the inhibitory effects of these compounds from our study should be experimentally validated against SARS-CoV-2. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.16574346.v1
title: <i>In silico</i> prediction of natural compounds as potential multi-target inhibitors of structural proteins of SARS-CoV-2

description: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a colossal loss to human health and lives and has deeply impacted socio-economic growth. Remarkable efforts have been made by the scientific community in containing the virus by successful development of vaccines and diagnostic kits. Initiatives towards drug repurposing and discovery have also been undertaken. In this study, we compiled the known natural anti-viral compounds using text mining of the literature and examined them against four major structural proteins of SARS-CoV-2, namely, spike (S) protein, nucleocapsid (N) protein, membrane (M) protein and envelope (E) protein. Following computational approaches, we identified fangchinoline and versicolactone C as the compounds to exhibit strong binding to the target proteins and causing structural deformation of three structural proteins (N, S and M). We recommend the inhibitory effects of these compounds from our study should be experimentally validated against SARS-CoV-2. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.16545924.v1
title: Immunoinformatic approach employing modeling and simulation to design a novel vaccine construct targeting MDR efflux pumps to confer wide protection against typhoidal <i>Salmonella</i> serovars

description: Overcoming multi drug resistance is one of the crucial challenges to control enteric typhoid fever caused by <i>Salmonella typhi</i> and <i>Salmonella paratyphi.</i> Overexpression of efflux pumps predominantly causes drug resistance in microorganisms. Therefore, immunotherapy targeting the various efflux pumps antigens could be a promising strategy to increase the success of vaccines. An immunoinformatic approach was employed to design a Salmonellosis multi-epitope subunit vaccine peptide consisting of linear B-cell and T-cell epitopes of multidrug resistance protein families including ATP Binding Cassette (ABC), major facilitator superfamily (MFS), resistance nodulation cell division (RND), small multidrug resistance (SMR), and multidrug and toxin extrusion (MATE). The selected epitopes exhibited conservation in both <i>S. typhi</i> and <i>S. paratyphi</i> and thus could be helpful for cross-protection. Further, the final vaccine construct encompassing the peptides, adjuvants and specific linker sequences showed high immunogenicity, solubility, non-allergenic, nontoxic, and wide population coverage due to strong binding affinity to maximum HLA alleles. The three-dimensional structure was predicted, and validated using various structure validation tools. Additionally, protein-protein docking of the chimeric vaccine construct with the TLR-2 protein and molecular dynamics demonstrated stable and efficient binding. Conclusively, the immunoinformatic study showed that the novel multi epitopic vaccine construct can simulate the both T-cell and B-cell immune responses in typhoidal Salmonella serovars and could potentially be used for prophylactic or therapeutic applications. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.16545924
title: Immunoinformatic approach employing modeling and simulation to design a novel vaccine construct targeting MDR efflux pumps to confer wide protection against typhoidal <i>Salmonella</i> serovars

description: Overcoming multi drug resistance is one of the crucial challenges to control enteric typhoid fever caused by <i>Salmonella typhi</i> and <i>Salmonella paratyphi.</i> Overexpression of efflux pumps predominantly causes drug resistance in microorganisms. Therefore, immunotherapy targeting the various efflux pumps antigens could be a promising strategy to increase the success of vaccines. An immunoinformatic approach was employed to design a Salmonellosis multi-epitope subunit vaccine peptide consisting of linear B-cell and T-cell epitopes of multidrug resistance protein families including ATP Binding Cassette (ABC), major facilitator superfamily (MFS), resistance nodulation cell division (RND), small multidrug resistance (SMR), and multidrug and toxin extrusion (MATE). The selected epitopes exhibited conservation in both <i>S. typhi</i> and <i>S. paratyphi</i> and thus could be helpful for cross-protection. Further, the final vaccine construct encompassing the peptides, adjuvants and specific linker sequences showed high immunogenicity, solubility, non-allergenic, nontoxic, and wide population coverage due to strong binding affinity to maximum HLA alleles. The three-dimensional structure was predicted, and validated using various structure validation tools. Additionally, protein-protein docking of the chimeric vaccine construct with the TLR-2 protein and molecular dynamics demonstrated stable and efficient binding. Conclusively, the immunoinformatic study showed that the novel multi epitopic vaccine construct can simulate the both T-cell and B-cell immune responses in typhoidal Salmonella serovars and could potentially be used for prophylactic or therapeutic applications. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.15121223
title: A combinatorial approach to screen structurally diverse acetylcholinesterase inhibitory plant secondary metabolites targeting Alzheimer’s disease

description: Alzheimer's disease (AD) is a form of Dementia known to diminish the brain's function by perturbating its structural and functional components. Though cholinesterase inhibitors are widely used to treat AD, they are limited by numbers and side effects. Hence, present study aims to identify structurally diverse Acetylcholinesterase (AChE) inhibitory plant secondary metabolites (PSM) by employing high throughput screening and computational studies. AChE inhibitory activity was performed using 390 crude extracts from 63 plant parts belongs to 58 plants. The lowest IC<sub>50</sub> value was recorded by acetone extract of <i>Cyperus rotundus</i> rhizome at 0.5 mg/ml, followed by methanol extract of <i>Terminalia arjuna</i> bark (0.95 mg/ml) and water extract <i>Acacia catechu</i> stem (0.95 mg/ml). A virtual library containing 487 PSM belongs to 18 plants found positive for AChE inhibition (IC<sub>50</sub>≤5 mg/ml) was prepared. Through ADMET analysis, 78 PSM fulfilling selected drug-likeness parameters were selected for further analysis. Molecular docking studies of selected PSM against AChE recorded a wide range of binding energy from −3.40 to −10.90 Kcal/mol. Further molecular dynamics simulation studies also recorded stabilized interactions of AChE-ligand complexes in the term of RMSD, RMSF, Rg, SASA, and hydrogen bond interaction. MMPBSA analysis revealed the binding energy of selected PSM ranging from −123.757 to −261.697 kJ/mol. Our study demonstrated the potential of 12 PSM (Sugiol, Margolone, 7-Hydroxy-3',4’-(Methylenedioxy) flavan, Beta-cyprone, Ethenone, Isomargolonone, Serpentine, Cryptolepine, Rotundone, Strictamin, Rotundenol and Nootkatone) as AChE inhibitors. Further <i>in vitro</i> and <i>in vivo</i> experimental evaluations with pure PSM could be beneficial for therapeutic uses. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.15121223.v1
title: A combinatorial approach to screen structurally diverse acetylcholinesterase inhibitory plant secondary metabolites targeting Alzheimer’s disease

description: Alzheimer's disease (AD) is a form of Dementia known to diminish the brain's function by perturbating its structural and functional components. Though cholinesterase inhibitors are widely used to treat AD, they are limited by numbers and side effects. Hence, present study aims to identify structurally diverse Acetylcholinesterase (AChE) inhibitory plant secondary metabolites (PSM) by employing high throughput screening and computational studies. AChE inhibitory activity was performed using 390 crude extracts from 63 plant parts belongs to 58 plants. The lowest IC<sub>50</sub> value was recorded by acetone extract of <i>Cyperus rotundus</i> rhizome at 0.5 mg/ml, followed by methanol extract of <i>Terminalia arjuna</i> bark (0.95 mg/ml) and water extract <i>Acacia catechu</i> stem (0.95 mg/ml). A virtual library containing 487 PSM belongs to 18 plants found positive for AChE inhibition (IC<sub>50</sub>≤5 mg/ml) was prepared. Through ADMET analysis, 78 PSM fulfilling selected drug-likeness parameters were selected for further analysis. Molecular docking studies of selected PSM against AChE recorded a wide range of binding energy from −3.40 to −10.90 Kcal/mol. Further molecular dynamics simulation studies also recorded stabilized interactions of AChE-ligand complexes in the term of RMSD, RMSF, Rg, SASA, and hydrogen bond interaction. MMPBSA analysis revealed the binding energy of selected PSM ranging from −123.757 to −261.697 kJ/mol. Our study demonstrated the potential of 12 PSM (Sugiol, Margolone, 7-Hydroxy-3',4’-(Methylenedioxy) flavan, Beta-cyprone, Ethenone, Isomargolonone, Serpentine, Cryptolepine, Rotundone, Strictamin, Rotundenol and Nootkatone) as AChE inhibitors. Further <i>in vitro</i> and <i>in vivo</i> experimental evaluations with pure PSM could be beneficial for therapeutic uses. Communicated by Ramaswamy H. Sarma