cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.16663357
title: <i>In silico</i> and <i>in vitro</i> assays reveal potential inhibitors against 3CL<i><sup>pro</sup></i> main protease of SARS-CoV-2

description: The COVID-19 pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not showing any sign of slowing down even after the ongoing efforts of vaccination. The threats of new strains are concerning, as some of them are more infectious than the original one. A therapeutic against the disease is, therefore, of urgent need. Here, we use the DrugBank database to screen for potential inhibitors against the 3CL<i><sup>pro</sup></i> main protease of SARS-CoV-2. Instead of using the traditional approach of computational screening by docking, we developed a kernel ridge regressor (using a part of the docking data) to predict the binding energy of ligands. We used this model to screen the DrugBank database and shortlist two lead candidates (bromocriptine and avoralstat) for <i>in vitro</i> enzymatic study. Our results show that the 3CL<i><sup>pro</sup></i> enzyme activity in presence of 100 <i>μ</i>M concentration of bromocriptine and avoralstat is 9.9% and 15.9%, respectively. Remarkably, bromocriptine exhibited submicromolar IC<sub>50</sub> of 130 nM (0.13 <i>μ</i>M). Avoralstat showed an IC<sub>50</sub> of 2.16 <i>μ</i>M. Further, the interactions of both drugs with 3CL<i><sup>pro</sup></i> were analyzed using molecular dynamics simulations of 100 ns. Results indicate that both ligands are stable in the binding pocket of the 3CL<i><sup>pro</sup></i> receptor. In addition, the MM-PBSA analysis revealed that bromocriptine (-29.37 kcal/mol) has a lower binding free energy compared to avoralstat (-6.91 kcal/mol). Further, hydrogen bond analysis also showed that bromocriptine interacts with the two catalytic residues, His<sup>41</sup> and Cys<sup>145</sup>, more frequently than avoralstat. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.16663357.v2
title: <i>In silico</i> and <i>in vitro</i> assays reveal potential inhibitors against 3CL<i><sup>pro</sup></i> main protease of SARS-CoV-2

description: The COVID-19 pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not showing any sign of slowing down even after the ongoing efforts of vaccination. The threats of new strains are concerning, as some of them are more infectious than the original one. A therapeutic against the disease is, therefore, of urgent need. Here, we use the DrugBank database to screen for potential inhibitors against the 3CL<i><sup>pro</sup></i> main protease of SARS-CoV-2. Instead of using the traditional approach of computational screening by docking, we developed a kernel ridge regressor (using a part of the docking data) to predict the binding energy of ligands. We used this model to screen the DrugBank database and shortlist two lead candidates (bromocriptine and avoralstat) for <i>in vitro</i> enzymatic study. Our results show that the 3CL<i><sup>pro</sup></i> enzyme activity in presence of 100 <i>μ</i>M concentration of bromocriptine and avoralstat is 9.9% and 15.9%, respectively. Remarkably, bromocriptine exhibited submicromolar IC<sub>50</sub> of 130 nM (0.13 <i>μ</i>M). Avoralstat showed an IC<sub>50</sub> of 2.16 <i>μ</i>M. Further, the interactions of both drugs with 3CL<i><sup>pro</sup></i> were analyzed using molecular dynamics simulations of 100 ns. Results indicate that both ligands are stable in the binding pocket of the 3CL<i><sup>pro</sup></i> receptor. In addition, the MM-PBSA analysis revealed that bromocriptine (-29.37 kcal/mol) has a lower binding free energy compared to avoralstat (-6.91 kcal/mol). Further, hydrogen bond analysis also showed that bromocriptine interacts with the two catalytic residues, His<sup>41</sup> and Cys<sup>145</sup>, more frequently than avoralstat. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.16668596
title: Clinically significant findings of high-risk mutations in human SLC29A4 gene associated with diabetes mellitus type 2 in Pakistani population

description: This study conducted an in-depth analysis combining computational and experimental verifications of the deleterious missense mutations associated with the SLC29A4 protein. The functional annotation of the non-synonymous single nucleotide polymorphism (nsSNPs), followed by structure-function analysis, revealed 13 single nucleotide polymorphisms (SNP) as the most damaging. Among these, six mutants P429T/S, L144S, M108V, N86H, and V79E, were predicted as structurally and functionally damaging by protein stability analysis. Also, these variants are located at evolutionary conserved regions, either buried, contributing to the structural damage, or exposed, causing functional changes in the protein. These mutants were further taken for molecular docking studies. When verified via experimental analysis, the SNPs M108V (rs149798710), N86H (rs151039853), and V79E (rs17854505) showed an association with type 2 diabetes mellitus (T2DM). Minor allele frequency for rs149798710 (A &gt; G) was 0.23 in controls, 0.29 in metformin responders, 0.37 in metformin non-responder, for rs151039853 (A &gt; C) was 0.21 in controls, 0.28 in metformin responders, 0.36 in metformin non-responder and for rs17854505 (T &gt; A) was 0.20 in controls, 0.25 in metformin responders, 0.37 in metformin non-responder. Hence, this study concludes that SLC29A4 M108V (rs149798710), N86H (rs151039853), and V79E (rs17854505) polymorphisms were associated with the increased risk of T2DM as well as with the increased risk towards the failure of metformin therapeutic response in T2DM patients of Pakistan. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.16668596.v1
title: Clinically significant findings of high-risk mutations in human SLC29A4 gene associated with diabetes mellitus type 2 in Pakistani population

description: This study conducted an in-depth analysis combining computational and experimental verifications of the deleterious missense mutations associated with the SLC29A4 protein. The functional annotation of the non-synonymous single nucleotide polymorphism (nsSNPs), followed by structure-function analysis, revealed 13 single nucleotide polymorphisms (SNP) as the most damaging. Among these, six mutants P429T/S, L144S, M108V, N86H, and V79E, were predicted as structurally and functionally damaging by protein stability analysis. Also, these variants are located at evolutionary conserved regions, either buried, contributing to the structural damage, or exposed, causing functional changes in the protein. These mutants were further taken for molecular docking studies. When verified via experimental analysis, the SNPs M108V (rs149798710), N86H (rs151039853), and V79E (rs17854505) showed an association with type 2 diabetes mellitus (T2DM). Minor allele frequency for rs149798710 (A &gt; G) was 0.23 in controls, 0.29 in metformin responders, 0.37 in metformin non-responder, for rs151039853 (A &gt; C) was 0.21 in controls, 0.28 in metformin responders, 0.36 in metformin non-responder and for rs17854505 (T &gt; A) was 0.20 in controls, 0.25 in metformin responders, 0.37 in metformin non-responder. Hence, this study concludes that SLC29A4 M108V (rs149798710), N86H (rs151039853), and V79E (rs17854505) polymorphisms were associated with the increased risk of T2DM as well as with the increased risk towards the failure of metformin therapeutic response in T2DM patients of Pakistan. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.16663357.v1
title: <i>In silico</i> and <i>in vitro</i> assays reveal potential inhibitors against 3CL<i><sup>pro</sup></i> main protease of SARS-CoV-2

description: The COVID-19 pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not showing any sign of slowing down even after the ongoing efforts of vaccination. The threats of new strains are concerning, as some of them are more infectious than the original one. A therapeutic against the disease is, therefore, of urgent need. Here, we use the DrugBank database to screen for potential inhibitors against the 3CL<i><sup>pro</sup></i> main protease of SARS-CoV-2. Instead of using the traditional approach of computational screening by docking, we developed a kernel ridge regressor (using a part of the docking data) to predict the binding energy of ligands. We used this model to screen the DrugBank database and shortlist two lead candidates (bromocriptine and avoralstat) for <i>in vitro</i> enzymatic study. Our results show that the 3CL<i><sup>pro</sup></i> enzyme activity in presence of 100 <i>μ</i>M concentration of bromocriptine and avoralstat is 9.9% and 15.9%, respectively. Remarkably, bromocriptine exhibited submicromolar IC<sub>50</sub> of 130 nM (0.13 <i>μ</i>M). Avoralstat showed an IC<sub>50</sub> of 2.16 <i>μ</i>M. Further, the interactions of both drugs with 3CL<i><sup>pro</sup></i> were analyzed using molecular dynamics simulations of 100 ns. Results indicate that both ligands are stable in the binding pocket of the 3CL<i><sup>pro</sup></i> receptor. In addition, the MM-PBSA analysis revealed that bromocriptine (-29.37 kcal/mol) has a lower binding free energy compared to avoralstat (-6.91 kcal/mol). Further, hydrogen bond analysis also showed that bromocriptine interacts with the two catalytic residues, His<sup>41</sup> and Cys<sup>145</sup>, more frequently than avoralstat. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.16616255
title: Structure-based virtual screening and molecular dynamics simulation for the identification of sphingosine kinase-2 inhibitors as potential analgesics

description: Neuropathic pain is due to an injury or disease of the somatosensory nervous system, which accounts for a significant economical and health burden to society. Due to poor understanding of their underlying mechanisms, the available treatments merely provide symptomatic relief and precipitates a variety of adverse effects. This suggests that there is an unmet medical need that must be addressed with effective strategies for the development of novel therapeutics. Sphingosine kinase 2 (SphK2) is an oncogenic lipid kinase that has emerged as a promising target for chronic pain and other diseases. In the present study, we have explored the structure-based virtual high-throughput screening of the Nuclei of Bioassays, Ecophysiology, and Biosynthesis of Natural Products Database (NuBBE) to identify potent natural products as inhibitors of SphK2. A molecular docking study was performed to calculate binding affinities and specificity to identify potential leads against SphK2. Initially, hits were selected by the implementation of absorption, distribution, metabolism, excretion and toxicity properties, Lipinski rule, and PAINS filters. The top-scoring hits also exhibiting an optimal ADMET profile were subjected to MM/GBSA free binding free energy calculation and molecular dynamics simulation. The results from molecular dynamics simulation revealed a stable ligand -SphK2 complex with protein and ligand RMSD within reasonable limits. Overall, we identified compounds, NuBBE_972 and NuBBE_1107 as potential inhibitors of SphK2 with optimal pharmacokinetic properties which have the potential to be developed as novel therapeutics for the management of chronic pain. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.16627748
title: <i>In silico</i> approach to design a multi-epitopic vaccine candidate targeting the non-mutational immunogenic regions in envelope protein and surface glycoprotein of SARS-CoV-2

description: The novel corona virus (COVID-19) is a causative agent for severe acute respiratory syndrome (SARS-CoV-2) and responsible for the current human pandemic situation which has caused global social and economic commotion. The currently available vaccines use whole viruses whereas there is scope for peptide based vaccines. Thus, the global raise in statistics of this infection at an alarming rate evoked us to determine a novel and effective vaccine candidate against SARS-CoV-2. To find the potential vaccine candidate targets, immunoinformatics approaches were used to analyze the mutations in the envelope protein and surface glycoprotein and determine the conserved region; further specific T-cell epitopes <i>VSLVKPSFY, SLVKPSFYV, RVKNLNSSR, SEETGTLIV, LVKPSFYVY, LTDEMIAQY, YLQPRTFLL, RLFRKSNLK, SPRRARSVA, AEIRASANL, TLLALHRSY, YSRVKNLNS</i> and <i>FELLHAPAT</i> and B-cells epitopes <i>TLAILTALRLCAYCCN</i> and <i>AGTITSGWTFGAGAAL</i> were identified. The 3 D structure of epitope was predicted, refined and validated. The molecular docking analysis of multi-epitope vaccine candidates with TLR receptors, predicted effective binding. Overall, using bioinformatics approach this multi-epitopic target facilitates the proof of concept for SARS-CoV-2 conserved epitopic vaccine design. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.16627748.v1
title: <i>In silico</i> approach to design a multi-epitopic vaccine candidate targeting the non-mutational immunogenic regions in envelope protein and surface glycoprotein of SARS-CoV-2

description: The novel corona virus (COVID-19) is a causative agent for severe acute respiratory syndrome (SARS-CoV-2) and responsible for the current human pandemic situation which has caused global social and economic commotion. The currently available vaccines use whole viruses whereas there is scope for peptide based vaccines. Thus, the global raise in statistics of this infection at an alarming rate evoked us to determine a novel and effective vaccine candidate against SARS-CoV-2. To find the potential vaccine candidate targets, immunoinformatics approaches were used to analyze the mutations in the envelope protein and surface glycoprotein and determine the conserved region; further specific T-cell epitopes <i>VSLVKPSFY, SLVKPSFYV, RVKNLNSSR, SEETGTLIV, LVKPSFYVY, LTDEMIAQY, YLQPRTFLL, RLFRKSNLK, SPRRARSVA, AEIRASANL, TLLALHRSY, YSRVKNLNS</i> and <i>FELLHAPAT</i> and B-cells epitopes <i>TLAILTALRLCAYCCN</i> and <i>AGTITSGWTFGAGAAL</i> were identified. The 3 D structure of epitope was predicted, refined and validated. The molecular docking analysis of multi-epitope vaccine candidates with TLR receptors, predicted effective binding. Overall, using bioinformatics approach this multi-epitopic target facilitates the proof of concept for SARS-CoV-2 conserved epitopic vaccine design. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.16577430.v2
title: Design, synthesis and evaluation of novel β-carboline ester analogues as potential anti-leishmanial agents

description: Leishmaniasis is one of today's most neglected diseases. The emergence of new anti-leishmanial therapies emphasizes several study groups funded by the World Health Organization. The present investigation will focus on the research to determine a few new potential derivatives of β-carboline ester derivatives against leishmaniasis. The <i>in-silico</i> predicted ADMET properties of most of the titled compounds are in an acceptable range and having drug like properties. Among all the tested analogs, compound <b>ES-3</b> (EC<sub>50</sub> 3.36 μM; SI &gt; 29.80) showed comparable and equipotent anti-leishmanial activity as that of standard drug miltefosine (EC<sub>50</sub> 4.80 μM; SI &gt; 20.80) against amastigote forms of the tested <i>L. infantum</i> strain. Two compounds <b>ES-6</b> and <b>ES-10</b> exhibited significant activity with EC<sub>50</sub> 10.16, 13.56 μM; SI &gt; 4.90, 7.37, respectively. <i>In-silico</i> based molecular docking and dynamics study of the significantly active analog also performed to study the putative binding mode, interaction pattern at the active site of the target leishmanial trypanothione reductase enzyme as well as stability of the target-ligand complex. The changes in the conformation of molecules during MD (frame wise trajectory analysis) provided new insights for the development of novel potent molecules. These findings will further give insight that will help modify the compound <b>ES-3</b> for better potency and the design of novel inhibitors for leishmaniasis. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.16616255.v1
title: Structure-based virtual screening and molecular dynamics simulation for the identification of sphingosine kinase-2 inhibitors as potential analgesics

description: Neuropathic pain is due to an injury or disease of the somatosensory nervous system, which accounts for a significant economical and health burden to society. Due to poor understanding of their underlying mechanisms, the available treatments merely provide symptomatic relief and precipitates a variety of adverse effects. This suggests that there is an unmet medical need that must be addressed with effective strategies for the development of novel therapeutics. Sphingosine kinase 2 (SphK2) is an oncogenic lipid kinase that has emerged as a promising target for chronic pain and other diseases. In the present study, we have explored the structure-based virtual high-throughput screening of the Nuclei of Bioassays, Ecophysiology, and Biosynthesis of Natural Products Database (NuBBE) to identify potent natural products as inhibitors of SphK2. A molecular docking study was performed to calculate binding affinities and specificity to identify potential leads against SphK2. Initially, hits were selected by the implementation of absorption, distribution, metabolism, excretion and toxicity properties, Lipinski rule, and PAINS filters. The top-scoring hits also exhibiting an optimal ADMET profile were subjected to MM/GBSA free binding free energy calculation and molecular dynamics simulation. The results from molecular dynamics simulation revealed a stable ligand -SphK2 complex with protein and ligand RMSD within reasonable limits. Overall, we identified compounds, NuBBE_972 and NuBBE_1107 as potential inhibitors of SphK2 with optimal pharmacokinetic properties which have the potential to be developed as novel therapeutics for the management of chronic pain. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.16577430
title: Design, synthesis and evaluation of novel β-carboline ester analogues as potential anti-leishmanial agents

description: Leishmaniasis is one of today's most neglected diseases. The emergence of new anti-leishmanial therapies emphasizes several study groups funded by the World Health Organization. The present investigation will focus on the research to determine a few new potential derivatives of β-carboline ester derivatives against leishmaniasis. The <i>in-silico</i> predicted ADMET properties of most of the titled compounds are in an acceptable range and having drug like properties. Among all the tested analogs, compound <b>ES-3</b> (EC<sub>50</sub> 3.36 μM; SI &gt; 29.80) showed comparable and equipotent anti-leishmanial activity as that of standard drug miltefosine (EC<sub>50</sub> 4.80 μM; SI &gt; 20.80) against amastigote forms of the tested <i>L. infantum</i> strain. Two compounds <b>ES-6</b> and <b>ES-10</b> exhibited significant activity with EC<sub>50</sub> 10.16, 13.56 μM; SI &gt; 4.90, 7.37, respectively. <i>In-silico</i> based molecular docking and dynamics study of the significantly active analog also performed to study the putative binding mode, interaction pattern at the active site of the target leishmanial trypanothione reductase enzyme as well as stability of the target-ligand complex. The changes in the conformation of molecules during MD (frame wise trajectory analysis) provided new insights for the development of novel potent molecules. These findings will further give insight that will help modify the compound <b>ES-3</b> for better potency and the design of novel inhibitors for leishmaniasis. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.16577430.v1
title: Design, synthesis and evaluation of novel β-carboline ester analogues as potential anti-leishmanial agents

description: Leishmaniasis is one of today's most neglected diseases. The emergence of new anti-leishmanial therapies emphasizes several study groups funded by the World Health Organization. The present investigation will focus on the research to determine a few new potential derivatives of β-carboline ester derivatives against leishmaniasis. The <i>in-silico</i> predicted ADMET properties of most of the titled compounds are in an acceptable range and having drug like properties. Among all the tested analogs, compound <b>ES-3</b> (EC<sub>50</sub> 3.36 μM; SI &gt; 29.80) showed comparable and equipotent anti-leishmanial activity as that of standard drug miltefosine (EC<sub>50</sub> 4.80 μM; SI &gt; 20.80) against amastigote forms of the tested <i>L. infantum</i> strain. Two compounds <b>ES-6</b> and <b>ES-10</b> exhibited significant activity with EC<sub>50</sub> 10.16, 13.56 μM; SI &gt; 4.90, 7.37, respectively. <i>In-silico</i> based molecular docking and dynamics study of the significantly active analog also performed to study the putative binding mode, interaction pattern at the active site of the target leishmanial trypanothione reductase enzyme as well as stability of the target-ligand complex. The changes in the conformation of molecules during MD (frame wise trajectory analysis) provided new insights for the development of novel potent molecules. These findings will further give insight that will help modify the compound <b>ES-3</b> for better potency and the design of novel inhibitors for leishmaniasis. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.16616635
title: Drug repositioning against COVID-19: a first line treatment

description: COVID-19 disease caused by the SARS-CoV-2 virus has shaken our health and wealth foundations. Although COVID-19 vaccines will become available allowing for attenuation of disease progression rates, distribution of vaccines can create other challenges and delays. Hence repurposed drugs against SARS-CoV-2 can be an attractive parallel strategy that can be integrated into routine clinical practice even in poorly-resourced countries. The present study was designed using knowledge of viral pathogenesis and pharmacodynamics of broad-spectrum antiviral agents (BSAAs). We carried out the virtual screening of BSAAs against the SARS-CoV-2 spike glycoprotein, RNA dependent RNA polymerase (RdRp), the main protease (Mpro) and the helicase enzyme of SARS-CoV-2. Imatinib (a tyrosine kinase inhibitor), Suramin (an anti-parasitic), Glycyrrhizin (an anti-inflammatory) and Bromocriptine (a dopamine agonist) showed higher binding affinity to multiple targets. Further through molecular dynamics simulation, critical conformational changes in the target protein molecules were revealed upon drug binding which illustrates the favorable binding conformations of antiviral drugs against SARS-CoV-2 target proteins. The resulting drugs from the present study in combination and in cocktails from the arsenal of existing drugs could reduce the translational distance and could offer substantial clinical benefit to decrease the burden of COVID-19 illness. This also creates a roadmap for subsequent viral diseases that emerge. Communicated by Ramaswamy H. Sarma