cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.19096223
title: Inhibition and disintegration of <i>Bacillus subtilis</i> biofilm with small molecule inhibitors identified through virtual screening for targeting TasA<sub>(28-261)</sub>, the major protein component of ECM

description: Microbial biofilms have been recognized for a vital role in antibiotic resistance and chronic microbial infections for 2-3 decades; still, there are no 'anti-biofilm drugs' available for human applications. There is an urgent need to develop novel 'anti-biofilms' therapeutics to manage biofilm-associated infectious diseases. Several reports have suggested that targeting molecules involved in quorum sensing or biofilm-specific transcription may inhibit biofilm formation. However, the possibility of targeting other vital components of microbial biofilms, especially the extracellular matrix (ECM) components, has remained largely unexplored. Here we report targeting TasA<sub>(28-261)</sub>, the major proteinaceous component of <i>Bacillus subtilis</i> ECM with two small molecule inhibitors (lovastatin and simvastatin) identified through virtual screening and drug repurposing, resulted in complete inhibition of biofilm. In molecular docking and dynamics simulation studies, lovastatin was observed to make stable interactions with TasA<sub>(28-261)</sub>, whereas the simvastatin – TasA<sub>(28-261)</sub> interactions were relatively less stable. However, in subsequent <i>in vitro</i> studies, both lovastatin and simvastatin successfully inhibited <i>B. subtilis</i> biofilm formation at MIC values of &lt; 10 µg/ml. Besides, these potential inhibitors also caused the disintegration of pre-formed biofilms. Results presented here provide ‘proof of concept’ for the hypothesis that targeting the extracellular matrix's vital component(s) could be one of the most efficient approaches for inhibiting microbial biofilms and disintegrating the pre-formed biofilms. We propose that a similar approach targeting ECM-associated proteins with FDA-approved drugs could be implemented to develop novel anti-biofilm therapeutic strategies against biofilm-forming chronic microbial pathogens. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.18750288.v1
title: An <i>in-silico</i> analysis to identify structural, functional and regulatory role of SNPs in <i>hMRE11</i>

description: Meiotic recombination 11 (<i>MRE11</i>) is a component of the tri-molecular <i>MRE11</i>-RAD50-NBS1 (MRN) complex, which functions as an exonuclease and endonuclease which is involved in identifying, signalling, protecting and repairing double-strand breaks in DNA (DSBs). Ataxia-telangiectasia-like disorder (ATLD) 1 and Nijmegen breakage syndrome (NBS)-like disorder are <i>MRE11</i> associated diseases. In the present study, we used an integrated computational approach to identify the most deleterious SNPs and their structural and functional impact on human <i>MRE11</i>. Five of the 68 observed non-synonymous SNP (nsSNPs; I162T, S273C, W210C, D311Y and R364L) should be worked on due to their strong possible pathogenicity and the risk of changing protein properties. All the nsSNPs were highly conserved and decrease the protein stability located in the <i>MRE11</i> nuclease and <i>MRE11</i> DNA binding presumed domain. R364L and I162T were predicted to be involved in post-translational modification (PTM) sites. Furthermore, we also analysed the regulatory effect of noncoding SNPs on <i>MRE11</i> gene regulation in which 6 SNPs were found to affect gene regulation. All six noncoding SNPs predicted chromatin interactive site whereas only one SNP was noted its association with miRNA binding site which disrupts 5 miRNA conserved site. These findings help future studies to get more insights into the role of these variants in the alteration of the <i>MRE11</i> function. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.19137525
title: Accelerating the discovery of the beyond rule of five compounds that have high affinities toward SARS-CoV-2 spike RBD

description: The battle against SARS-CoV-2 coronavirus is the focal point for the global pandemic that has affected millions of lives worldwide. The need for effective and selective therapeutics for the treatment of the disease caused by SARS-CoV-2 is critical. Herein, we performed a hierarchical computational approach incorporating molecular docking studies, molecular dynamics simulations, absolute binding energy calculations, and steered molecular dynamics simulations for the discovery of potential compounds with high affinity towards SARS-CoV-2 spike RBD. By leveraging ZINC15 database, a total of 1282 in-clinical and FDA approved drugs were filtered out from nearly 0.5 million protomers of relatively large compounds (MW &gt; 500, and LogP ≤ 5). Our results depict plausible mechanistic aspects related to the blockage of SARS-CoV-2 spike RBD by the top hits discovered. We found that the most promising candidates, namely, ZINC95628821, ZINC95617623, ZINC3979524, and ZINC261494658, strongly bind to the spike RBD and interfere with the human ACE2 receptor. These findings accelerate the rational design of selective inhibitors targeting the spike RBD protein of SARS-CoV-2. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.18865232
title: Repurposing FDA-approved drugs as HIV-1 integrase inhibitors: an <i>in silico</i> investigation

description: The Human Immunodeficiency Virus (HIV) infection is a global pandemic that has claimed 33 million lives to-date. One of the most efficacious treatments for naïve or pretreated HIV patients is the HIV integrase strand transfer inhibitors (INSTIs). However, given that HIV treatment is life-long, the emergence of HIV strains resistant to INSTIs is an imminent challenge. In this work, we showed two best regression QSAR models that were constructed using a boosted Random Forest algorithm (r<sup>2</sup> = 0.998, q<sup>2</sup><sub>10CV</sub> = 0.721, q<sup>2</sup><sub>external_test</sub> = 0.754) and a boosted K* algorithm (r<sup>2</sup> = 0.987, q<sup>2</sup><sub>10CV</sub> = 0.721, q<sup>2</sup><sub>external_test</sub> = 0.758) to predict the pIC<sub>50</sub> values of INSTIs. Subsequently, the regression QSAR models were deployed against the Drugbank database for drug repositioning. The top-ranked compounds were further evaluated for their target engagement activity using molecular docking studies and accelerated Molecular Dynamics simulation. Lastly, their potential as INSTIs were also evaluated from our literature search. Our study offers the first example of a large-scale regression QSAR modelling effort for discovering highly active INSTIs to combat HIV infection. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.19096223.v1
title: Inhibition and disintegration of <i>Bacillus subtilis</i> biofilm with small molecule inhibitors identified through virtual screening for targeting TasA<sub>(28-261)</sub>, the major protein component of ECM

description: Microbial biofilms have been recognized for a vital role in antibiotic resistance and chronic microbial infections for 2-3 decades; still, there are no 'anti-biofilm drugs' available for human applications. There is an urgent need to develop novel 'anti-biofilms' therapeutics to manage biofilm-associated infectious diseases. Several reports have suggested that targeting molecules involved in quorum sensing or biofilm-specific transcription may inhibit biofilm formation. However, the possibility of targeting other vital components of microbial biofilms, especially the extracellular matrix (ECM) components, has remained largely unexplored. Here we report targeting TasA<sub>(28-261)</sub>, the major proteinaceous component of <i>Bacillus subtilis</i> ECM with two small molecule inhibitors (lovastatin and simvastatin) identified through virtual screening and drug repurposing, resulted in complete inhibition of biofilm. In molecular docking and dynamics simulation studies, lovastatin was observed to make stable interactions with TasA<sub>(28-261)</sub>, whereas the simvastatin – TasA<sub>(28-261)</sub> interactions were relatively less stable. However, in subsequent <i>in vitro</i> studies, both lovastatin and simvastatin successfully inhibited <i>B. subtilis</i> biofilm formation at MIC values of &lt; 10 µg/ml. Besides, these potential inhibitors also caused the disintegration of pre-formed biofilms. Results presented here provide ‘proof of concept’ for the hypothesis that targeting the extracellular matrix's vital component(s) could be one of the most efficient approaches for inhibiting microbial biofilms and disintegrating the pre-formed biofilms. We propose that a similar approach targeting ECM-associated proteins with FDA-approved drugs could be implemented to develop novel anti-biofilm therapeutic strategies against biofilm-forming chronic microbial pathogens. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.19137525.v1
title: Accelerating the discovery of the beyond rule of five compounds that have high affinities toward SARS-CoV-2 spike RBD

description: The battle against SARS-CoV-2 coronavirus is the focal point for the global pandemic that has affected millions of lives worldwide. The need for effective and selective therapeutics for the treatment of the disease caused by SARS-CoV-2 is critical. Herein, we performed a hierarchical computational approach incorporating molecular docking studies, molecular dynamics simulations, absolute binding energy calculations, and steered molecular dynamics simulations for the discovery of potential compounds with high affinity towards SARS-CoV-2 spike RBD. By leveraging ZINC15 database, a total of 1282 in-clinical and FDA approved drugs were filtered out from nearly 0.5 million protomers of relatively large compounds (MW &gt; 500, and LogP ≤ 5). Our results depict plausible mechanistic aspects related to the blockage of SARS-CoV-2 spike RBD by the top hits discovered. We found that the most promising candidates, namely, ZINC95628821, ZINC95617623, ZINC3979524, and ZINC261494658, strongly bind to the spike RBD and interfere with the human ACE2 receptor. These findings accelerate the rational design of selective inhibitors targeting the spike RBD protein of SARS-CoV-2. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.18865232.v1
title: Repurposing FDA-approved drugs as HIV-1 integrase inhibitors: an <i>in silico</i> investigation

description: The Human Immunodeficiency Virus (HIV) infection is a global pandemic that has claimed 33 million lives to-date. One of the most efficacious treatments for naïve or pretreated HIV patients is the HIV integrase strand transfer inhibitors (INSTIs). However, given that HIV treatment is life-long, the emergence of HIV strains resistant to INSTIs is an imminent challenge. In this work, we showed two best regression QSAR models that were constructed using a boosted Random Forest algorithm (r<sup>2</sup> = 0.998, q<sup>2</sup><sub>10CV</sub> = 0.721, q<sup>2</sup><sub>external_test</sub> = 0.754) and a boosted K* algorithm (r<sup>2</sup> = 0.987, q<sup>2</sup><sub>10CV</sub> = 0.721, q<sup>2</sup><sub>external_test</sub> = 0.758) to predict the pIC<sub>50</sub> values of INSTIs. Subsequently, the regression QSAR models were deployed against the Drugbank database for drug repositioning. The top-ranked compounds were further evaluated for their target engagement activity using molecular docking studies and accelerated Molecular Dynamics simulation. Lastly, their potential as INSTIs were also evaluated from our literature search. Our study offers the first example of a large-scale regression QSAR modelling effort for discovering highly active INSTIs to combat HIV infection. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.19096214
title: Excavating phytochemicals from plants possessing antiviral activities for identifying SARS-CoV hemagglutinin-esterase inhibitors by diligent computational workflow

description: Coronaviruses (CoVs) belong to a group of RNA viruses that cause diseases in vertebrates including. Newer and deadlier than SARS CoV-2 are sought to appear in future for which the scientific community must be prepared with the strategies for their control. Spike protein (S-protein) of all the CoVs require angiotensin-converting enzyme2 (ACE2), while CoVs also require hemagglutinin-acetylesterase (HE) glycoprotein receptor to simultaneously interact with O-acetylated sialic acids on host cells, both these interactions enable viral particle to enter host cell leading to its infection. Target inhibition of viral S-protein and HE glycoprotein receptor can lead to a development of therapy against the SARS CoV-2. The proposition is to recognize molecules from the bundle of phytochemicals of medicinal plants known to possess antiviral potentials as a lead that could interact and mask the active site of, HE glycoprotein which would ideally bind to O-acetylated sialic acids on human host cells. Such molecules can be addressed as ‘HE glycoprotein blockers’. A library of 110 phytochemicals from <i>Withania somnifera</i>, <i>Asparagus racemosus</i>, <i>Zinziber officinalis</i>, <i>Allium sativum</i>, <i>Curcuma longa</i> and <i>Adhatoda vasica</i> was constructed and was used under present study. <i>In silico</i> analysis was employed with plant-derived phytochemicals. The molecular docking, molecular dynamics simulations over the scale of 1000 ns (1 μs) and ADMET prediction revealed that the <i>Withania somnifera</i> (ashwagandha) and <i>Asparagus racemosus</i> (shatavari) plants possessed various steroidal saponins and alkaloids which could potentially inhibit the COVID-19 virus and even other CoVs targeted HE glycoprotein receptor. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.19122198
title: Computational approaches for evaluation of isobavachin as potential inhibitor against t877a and w741l mutations in prostate cancer

description: Prostate cancer is the World’s second most common cancer, with the fifth-highest male mortality rate. Point mutations such as T877A and W741L are frequently seen in advanced prostate cancer patients, conferring drug-resistance and hence driving cancer growth. Such occurrence of drug resistance in prostate cancer necessitates designing of suitable ligands to ensure better interactions with the receptors which can block the progression of the disease. The present study focus on the modification of plant-derived flavonoids that might act as inhibitors against such point mutations namely, T877A and W741L. In T877A mutation threonine is substituted by alanine at the 877 codon and W741L mutation, tryptophan is substituted by lysine at the 741 codon in prostate cancer. The study revolved on the aspect of the evaluation of Isobavachin and its derivatives as a potential agent to tackle such point mutations by using the <i>in silico</i> approach. A total of 98 molecular dockings were performed to find the ligand-receptor complexes with the lowest binding energy employing Autodock Software to conduct the blind and site-specific docking. Additionally, ligands were screened for Drug-likeness and toxicity using several tools yielding eight possible drug candidates. Based on the results of Molecular Docking, Drug-likeness, and ADMET testing, ten structures, including six complexes and three receptors were subjected to molecular dynamics simulation of 100 ns covering RMSD, RMSF, Rg, and MM/PBSA. Based on the simulation results, Isobavachin, IsoMod4, and IsoMod7 were concluded to be stable and exhibited potential properties for developing a novel drug to combat prostate cancer and its associated drug-resistance. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.19122195
title: Computational studies on the cholinesterase, beta-secretase 1 (BACE1) and monoamine oxidase (MAO) inhibitory activities of endophytes-derived compounds: towards discovery of novel neurotherapeutics

description: Cholinesterases, beta-secretase 1 (BACE1) and monoamine oxidase (MAO) are significant in the etiology of neurodegenerative diseases. Inhibition of these enzymes is therefore a major strategy for the development of neurotherapeutics. Even though, this strategy has birthed some approved synthetic drugs, they are characterized by adverse effects. It is therefore, imperative to explore promising alternatives. Consequently, we assessed the inhibitory activities of some endophytes-derived compounds against selected targets towards discovery of novel neurotherapeutics. Standard inhibitors and 83 endophytes-derived compounds were docked against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), BACE 1 and MAO using AutodockVina while the molecular interactions between the selected targets and the compounds with notable binding affinity were viewed through Discovery Studio Visualizer. Druglikeness and Absorption–Distribution–Metabolism–Excretion-Toxicity (ADMET) and blood brain barrier (BBB) properties of the top 4 compounds were evaluated using the Swiss online ADME web tool and OSIRIS server; ligands-enzymes complex stability was assessed through molecular dynamics (MD) simulation. From the 83 compounds, asperflavin, ascomfurans C, camptothecine and corynesidone A exhibited remarkable inhibitory activity against all the four target enzymes compared to the respective standard inhibitors. However, only corynesidone A could transverse the BBB and predicted to be safe. MD simulation of the unbound and complexed enzymes with corynesidone A showed that the complexes were stable throughout the simulation time. Given the exceptional inhibitory activity of endophytes-derived corynesidone A against the four selected targets, its ability to permeate the BBB, excellent drugability properties as well as its stability when complexed with the enzymes, it is a good candidate for further studies towards development of new neurotherapeutics. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.19122198.v1
title: Computational approaches for evaluation of isobavachin as potential inhibitor against t877a and w741l mutations in prostate cancer

description: Prostate cancer is the World’s second most common cancer, with the fifth-highest male mortality rate. Point mutations such as T877A and W741L are frequently seen in advanced prostate cancer patients, conferring drug-resistance and hence driving cancer growth. Such occurrence of drug resistance in prostate cancer necessitates designing of suitable ligands to ensure better interactions with the receptors which can block the progression of the disease. The present study focus on the modification of plant-derived flavonoids that might act as inhibitors against such point mutations namely, T877A and W741L. In T877A mutation threonine is substituted by alanine at the 877 codon and W741L mutation, tryptophan is substituted by lysine at the 741 codon in prostate cancer. The study revolved on the aspect of the evaluation of Isobavachin and its derivatives as a potential agent to tackle such point mutations by using the <i>in silico</i> approach. A total of 98 molecular dockings were performed to find the ligand-receptor complexes with the lowest binding energy employing Autodock Software to conduct the blind and site-specific docking. Additionally, ligands were screened for Drug-likeness and toxicity using several tools yielding eight possible drug candidates. Based on the results of Molecular Docking, Drug-likeness, and ADMET testing, ten structures, including six complexes and three receptors were subjected to molecular dynamics simulation of 100 ns covering RMSD, RMSF, Rg, and MM/PBSA. Based on the simulation results, Isobavachin, IsoMod4, and IsoMod7 were concluded to be stable and exhibited potential properties for developing a novel drug to combat prostate cancer and its associated drug-resistance. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.19126593
title: Distribution of simple sequence repeats, transcription factors, and differentially expressed genes in the NGS-based transcriptome of male and female seabuckthorn (<i>Hippophae salicifolia</i>)

description: Seabuckthorn (<i>Hippophae salicifolia</i>) is a perennial, multipurpose wonder plant, popular for its immense medicinal, nutritional, and therapeutic properties. However, due to the lack of whole-genome-based studies, the molecular mechanism governing distinct sexual phenotypes is still not clear. We employed the high-throughput NGS Illumina NovaSeq paired-end technology to generate whole transcriptome profiles of male and female plants of <i>H. salicifolia</i>. In total, 3.2 million raw short reads were generated with an average length of 150 bp, including 50911358 reads from the male leaf tissue samples and 45850364 reads from the female leaf tissue samples. Clustering of the high-quality reads yielded <i>de novo</i> short read assembly of 50259 transcripts of &gt;100 bp length. The final transcripts were assigned Gene Ontology (GO) terms. The digital expression of genes was studied using the DESeq2 of R package that identified 7180 differentially expressed genes (DEGs) between the male and female plant samples. Further, 10,850 simple sequence repeats, and 8,351 transcription factors, distributed in more than 85 transcription families, were also mined from the final assembled transcriptome. Next, COG and KEGG pathway analyses were performed to assign biological functional terms to the DEGs. The findings of the present study will provide a valuable resource for gene expression discovery and other functional genomics studies aiming towards the selection of candidate genes for the development of sex-specific markers in seabuckthorn and other closely related species. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.19126593.v1
title: Distribution of simple sequence repeats, transcription factors, and differentially expressed genes in the NGS-based transcriptome of male and female seabuckthorn (<i>Hippophae salicifolia</i>)

description: Seabuckthorn (<i>Hippophae salicifolia</i>) is a perennial, multipurpose wonder plant, popular for its immense medicinal, nutritional, and therapeutic properties. However, due to the lack of whole-genome-based studies, the molecular mechanism governing distinct sexual phenotypes is still not clear. We employed the high-throughput NGS Illumina NovaSeq paired-end technology to generate whole transcriptome profiles of male and female plants of <i>H. salicifolia</i>. In total, 3.2 million raw short reads were generated with an average length of 150 bp, including 50911358 reads from the male leaf tissue samples and 45850364 reads from the female leaf tissue samples. Clustering of the high-quality reads yielded <i>de novo</i> short read assembly of 50259 transcripts of &gt;100 bp length. The final transcripts were assigned Gene Ontology (GO) terms. The digital expression of genes was studied using the DESeq2 of R package that identified 7180 differentially expressed genes (DEGs) between the male and female plant samples. Further, 10,850 simple sequence repeats, and 8,351 transcription factors, distributed in more than 85 transcription families, were also mined from the final assembled transcriptome. Next, COG and KEGG pathway analyses were performed to assign biological functional terms to the DEGs. The findings of the present study will provide a valuable resource for gene expression discovery and other functional genomics studies aiming towards the selection of candidate genes for the development of sex-specific markers in seabuckthorn and other closely related species. Communicated by Ramaswamy H. Sarma