cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.15138068.v1
title: Quantitative structure-activity relationships, molecular docking and molecular dynamics simulations reveal drug repurposing candidates as potent SARS-CoV-2 main protease inhibitors

description: The current outbreak of COVID-19 is leading an unprecedented scientific effort focusing on targeting SARS-CoV-2 proteins critical for its viral replication. Herein, we performed high-throughput virtual screening of more than eleven thousand FDA-approved drugs using backpropagation-based artificial neural networks (<i>q</i><sup>2</sup><sub>LOO</sub> = 0.60, <i>r</i><sup>2</sup> = 0.80 and <i>r</i><sup>2</sup><sub>pred</sub> = 0.91), partial-least-square (PLS) regression (<i>q</i><sup>2</sup><sub>LOO</sub> = 0.83, <i>r</i><sup>2</sup> = 0.62 and <i>r</i><sup>2</sup><sub>pred</sub> = 0.70) and sequential minimal optimization (SMO) regression (<i>q</i><sup>2</sup><sub>LOO</sub> = 0.70, <i>r</i><sup>2</sup> = 0.80 and <i>r</i><sup>2</sup><sub>pred</sub> = 0.89). We simulated the stability of Acarbose-derived hexasaccharide, Naratriptan, Peramivir, Dihydrostreptomycin, Enviomycin, Rolitetracycline, Viomycin, Angiotensin II, Angiotensin 1-7, Angiotensinamide, Fenoterol, Zanamivir, Laninamivir and Laninamivir octanoate with 3CL<sub>pro</sub> by 100 ns and calculated binding free energy using molecular mechanics combined with Poisson-Boltzmann surface area (MM-PBSA). Our QSAR models and molecular dynamics data suggest that seven repurposed-drug candidates such as Acarbose-derived Hexasaccharide, Angiotensinamide, Dihydrostreptomycin, Enviomycin, Fenoterol, Naratriptan and Viomycin are potential SARS-CoV-2 main protease inhibitors. In addition, our QSAR models and molecular dynamics simulations revealed that His41, Asn142, Cys145, Glu166 and Gln189 are potential pharmacophoric centers for 3CL<sub>pro</sub> inhibitors. Glu166 is a potential pharmacophore for drug design and inhibitors that interact with this residue may be critical to avoid dimerization of 3CL<sub>pro</sub>. Our results will contribute to future investigations of novel chemical scaffolds and the discovery of novel hits in high-throughput screening as potential anti-SARS-CoV-2 properties. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.14979603
title: Dietary factors and SARS-CoV-2 contagion: <i>in silico</i> studies on modulation of viral and host proteins by spice actives

description: The SARS-CoV-2 contagion has had a huge impact on world population. It has been observed that despite massive spread of the contagion in India particularly during the second wave, the overall case fatality rates remain low. This prompted us to look into dietary factors that can possibly modulate the viral impact and/or host response. In silico studies were carried out on forty-two commonly used spices and their 637 known active compounds with an aim of identifying such compounds that may have propensity to reduce viral impact or boost host immune response. We chose to study SARS-Cov-2 helicase on account of its functional importance in maintaining viral load within the host, and the human tank binding protein (TBK1) for its important role in host immunity. We carried out in silico virtual screening, docking studies with 637 phytochemical against these two proteins, using in silico methods. Upon assessing the strength of the ligand-target interactions and post simulation binding energy profile, our study identifies procyanidin-B4 from bay leaf, fenugreekine from fenugreek seed and gallotannin from pomegranate seed as active interactors that docked to viral helicase. Similarly, we identified eruboside B from garlic, gallotannin from pomegranate seed, as strong interacting partners to human TBK1. Our studies thus present dietary spice constituents as potential protagonists for further experimentation to understand how spices in the diet might help the hosts in countering the viral assault and mount a robust protective response against COVID and other infections. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.14979603.v1
title: Dietary factors and SARS-CoV-2 contagion: <i>in silico</i> studies on modulation of viral and host proteins by spice actives

description: The SARS-CoV-2 contagion has had a huge impact on world population. It has been observed that despite massive spread of the contagion in India particularly during the second wave, the overall case fatality rates remain low. This prompted us to look into dietary factors that can possibly modulate the viral impact and/or host response. In silico studies were carried out on forty-two commonly used spices and their 637 known active compounds with an aim of identifying such compounds that may have propensity to reduce viral impact or boost host immune response. We chose to study SARS-Cov-2 helicase on account of its functional importance in maintaining viral load within the host, and the human tank binding protein (TBK1) for its important role in host immunity. We carried out in silico virtual screening, docking studies with 637 phytochemical against these two proteins, using in silico methods. Upon assessing the strength of the ligand-target interactions and post simulation binding energy profile, our study identifies procyanidin-B4 from bay leaf, fenugreekine from fenugreek seed and gallotannin from pomegranate seed as active interactors that docked to viral helicase. Similarly, we identified eruboside B from garlic, gallotannin from pomegranate seed, as strong interacting partners to human TBK1. Our studies thus present dietary spice constituents as potential protagonists for further experimentation to understand how spices in the diet might help the hosts in countering the viral assault and mount a robust protective response against COVID and other infections. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.15090949
title: Evolving ribonucleocapsid assembly/packaging signals in the genomes of the human and animal coronaviruses: targeting, transmission and evolution

description: A world-wide COVID-19 pandemic intensified strongly the studies of molecular mechanisms related to the coronaviruses. The origin of coronaviruses and the risks of human-to-human, animal-to-human and human-to-animal transmission of coronaviral infections can be understood only on a broader evolutionary level by detailed comparative studies. In this paper, we studied ribonucleocapsid assembly-packaging signals (RNAPS) in the genomes of all seven known pathogenic human coronaviruses, SARS-CoV, SARS-CoV-2, MERS-CoV, HCoV-OC43, HCoV-HKU1, HCoV-229E and HCoV-NL63 and compared them with RNAPS in the genomes of the related animal coronaviruses including SARS-Bat-CoV, MERS-Camel-CoV, MHV, Bat-CoV MOP1, TGEV and one of camel alphacoronaviruses. RNAPS in the genomes of coronaviruses were evolved due to weakly specific interactions between genomic RNA and N proteins in helical nucleocapsids. Combining transitional genome mapping and Jaccard correlation coefficients allows us to perform the analysis directly in terms of underlying motifs distributed over the genome. In all coronaviruses, RNAPS were distributed quasi-periodically over the genome with the period about 54 nt biased to 57 nt and to 51 nt for the genomes longer and shorter than that of SARS-CoV, respectively. The comparison with the experimentally verified packaging signals for MERS-CoV, MHV and TGEV proved that the distribution of particular motifs is strongly correlated with the packaging signals. We also found that many motifs were highly conserved in both characters and positioning on the genomes throughout the lineages that make them promising therapeutic targets. The mechanisms of encapsidation can affect the recombination and co-infection as well. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.15090949.v1
title: Evolving ribonucleocapsid assembly/packaging signals in the genomes of the human and animal coronaviruses: targeting, transmission and evolution

description: A world-wide COVID-19 pandemic intensified strongly the studies of molecular mechanisms related to the coronaviruses. The origin of coronaviruses and the risks of human-to-human, animal-to-human and human-to-animal transmission of coronaviral infections can be understood only on a broader evolutionary level by detailed comparative studies. In this paper, we studied ribonucleocapsid assembly-packaging signals (RNAPS) in the genomes of all seven known pathogenic human coronaviruses, SARS-CoV, SARS-CoV-2, MERS-CoV, HCoV-OC43, HCoV-HKU1, HCoV-229E and HCoV-NL63 and compared them with RNAPS in the genomes of the related animal coronaviruses including SARS-Bat-CoV, MERS-Camel-CoV, MHV, Bat-CoV MOP1, TGEV and one of camel alphacoronaviruses. RNAPS in the genomes of coronaviruses were evolved due to weakly specific interactions between genomic RNA and N proteins in helical nucleocapsids. Combining transitional genome mapping and Jaccard correlation coefficients allows us to perform the analysis directly in terms of underlying motifs distributed over the genome. In all coronaviruses, RNAPS were distributed quasi-periodically over the genome with the period about 54 nt biased to 57 nt and to 51 nt for the genomes longer and shorter than that of SARS-CoV, respectively. The comparison with the experimentally verified packaging signals for MERS-CoV, MHV and TGEV proved that the distribution of particular motifs is strongly correlated with the packaging signals. We also found that many motifs were highly conserved in both characters and positioning on the genomes throughout the lineages that make them promising therapeutic targets. The mechanisms of encapsidation can affect the recombination and co-infection as well. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.15015480
title: Network pharmacological evaluation of <i>Withania somnifera</i> bioactive phytochemicals for identifying novel potential inhibitors against neurodegenerative disorder

description: Neurodegenerative disorders are illnesses that are responsible for neuronal cell death and resulting in lifelong cognitive problems. Due to their unclear mechanism, there are no effective drugs available for the treatment. For a long time, herbal drugs have been used as a role model in the field of the drug discovery process. <i>Withania somnifera</i> (Ashwagandha) in the Indian medicinal system (Ayurveda) is used for several neuronal disorders like insomnia and memory loss for decades. This study aims to identify active components of <i>W. somnifera</i> (WS) as potential inhibitors for the treatment of neurodegenerative diseases (ND). To fulfill this objective, Network pharmacology approach, gene ontology, pharmacokinetics analysis, molecular docking, and molecular dynamics simulation (MDS) studies were performed. A total of 77 active components in WS, 175 predicted neurodegenerative targets of WS, and 8085 ND-related targets were identified from different databases. The network analysis showed that the top ten targets APP, EGFR, MAPK1, ESR1, HSPA4, PRKCD, MAPK3, ABL1, JUN, and GSK3B were found as significant target related to ND. On the basis of gene ontology and topology analysis results, APP was found as a significant target related to Alzheimer’s disease pathways. Molecular docking results found that Anahygrine, Cuscohygrine, Isopelletierine, and Nicotine showed the best binding affinities −5.55, −4.73, −4.04, and −4.11 Kcal/mol. Further, MDS results suggested that Isopelletierine and Nicotine could be used as potential inhibitors against APP protein and could be useful for the treatment of Alzheimer’s disease. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.15015480.v1
title: Network pharmacological evaluation of <i>Withania somnifera</i> bioactive phytochemicals for identifying novel potential inhibitors against neurodegenerative disorder

description: Neurodegenerative disorders are illnesses that are responsible for neuronal cell death and resulting in lifelong cognitive problems. Due to their unclear mechanism, there are no effective drugs available for the treatment. For a long time, herbal drugs have been used as a role model in the field of the drug discovery process. <i>Withania somnifera</i> (Ashwagandha) in the Indian medicinal system (Ayurveda) is used for several neuronal disorders like insomnia and memory loss for decades. This study aims to identify active components of <i>W. somnifera</i> (WS) as potential inhibitors for the treatment of neurodegenerative diseases (ND). To fulfill this objective, Network pharmacology approach, gene ontology, pharmacokinetics analysis, molecular docking, and molecular dynamics simulation (MDS) studies were performed. A total of 77 active components in WS, 175 predicted neurodegenerative targets of WS, and 8085 ND-related targets were identified from different databases. The network analysis showed that the top ten targets APP, EGFR, MAPK1, ESR1, HSPA4, PRKCD, MAPK3, ABL1, JUN, and GSK3B were found as significant target related to ND. On the basis of gene ontology and topology analysis results, APP was found as a significant target related to Alzheimer’s disease pathways. Molecular docking results found that Anahygrine, Cuscohygrine, Isopelletierine, and Nicotine showed the best binding affinities −5.55, −4.73, −4.04, and −4.11 Kcal/mol. Further, MDS results suggested that Isopelletierine and Nicotine could be used as potential inhibitors against APP protein and could be useful for the treatment of Alzheimer’s disease. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.15082625
title: Validating the predictions of murburn model for oxygenic photosynthesis: Analyses of ligand-binding to protein complexes and cross-system comparisons

description: In this second half of our treatise on oxygenic photosynthesis, we provide support for the murburn model of the light reaction of photosynthesis and ratify key predictions made in the first part. Molecular docking and visualization of various ligands of quinones/quinols (and their derivatives) with PS II/Cytochrome <i>b</i><sub>6</sub><i>f</i> complexes did not support chartered 2e-transport role of quinols. A broad variety of herbicides did not show any affinity/binding-based rationales for inhibition of photosynthesis. We substantiate the proposal that disubstituted phenolics (perceived as protonophores/uncouplers or affinity-based inhibitors in the classical purview) serve as interfacial modulators of diffusible reactive (oxygen) species or DR(O)S. The DRS-based murburn model is evidenced by the identification of multiple ADP-binding sites on the extra-membraneous projection of protein complexes and structure/distribution of the photo/redox catalysts. With a panoramic comparison of the redox metabolic machinery across diverse organellar/cellular systems, we highlight the ubiquitous one-electron murburn facets (cofactors of porphyrin, flavin, FeS, other metal centers and photo/redox active pigments) that enable a facile harnessing of the utility of DRS. In the summative analyses, it is demonstrated that the murburn model of light reaction explains the structures of membrane supercomplexes recently observed in thylakoids and also accounts for several photodynamic experimental observations and evolutionary considerations. <i>In toto</i>, the work provides a new orientation and impetus to photosynthesis research. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.15164013
title: Identification of miRNAs and related hub genes associated with the triple negative breast cancer using integrated bioinformatics analysis and <i>in vitro</i> approach

description: Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype generally associated with younger women. Due to the lack of suitable drugable targets in TNBC, the microRNAs are considered as a better hope as therapeutic agents for the management of the disease. In this study, we identified differentially expressed miRNAs (DEMs) and associated hub genes in TNBC microarray data (GSE38167, GSE60714, and GSE10833) using bioinformatics tools. The identified miRNAs and genes were validated in the TNBC cell line model (MDA-MB-231) compared with the normal breast cells (MCF-10A) using the qRT-PCR technique. False-positive DEMs were avoided by comparing the DEMs profile of TNBC and triple positive breast cancer (TPBC) cell line model (BT474) compared with the MCF-10A cells data. In addition, we studied the effect of anticancer phytochemicals on the differential expression of miRNAs and genes in MDA-MB-231 cells. Furthermore, target predictions, functional enrichment and KEGG pathway analysis, mutation and copy number alterations, and overall survival analysis of DEMs in TNBC sample was investigated using standard computational tools. The study identifies first time the association of hsa-miR-1250, has-miR-1273, and has-miR-635 with the TNBC. DEMs showed significant association with the Wnt, ErbB, PI3-Akt and cAMP signaling pathways having clinical implications in TNBC tumorigenesis. The DEMs and hub genes (HOXC6 and ACVR2B) showed survival disadvantages in TNBC patients. In summary, the identified miRNAs and hub genes show important implications in TNBC tumorigenesis and patient survival. We recommend further experimental studies on pathophysiological mechanism of the identified miRNAs and hub genes in TNBC. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.15164013.v1
title: Identification of miRNAs and related hub genes associated with the triple negative breast cancer using integrated bioinformatics analysis and <i>in vitro</i> approach

description: Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype generally associated with younger women. Due to the lack of suitable drugable targets in TNBC, the microRNAs are considered as a better hope as therapeutic agents for the management of the disease. In this study, we identified differentially expressed miRNAs (DEMs) and associated hub genes in TNBC microarray data (GSE38167, GSE60714, and GSE10833) using bioinformatics tools. The identified miRNAs and genes were validated in the TNBC cell line model (MDA-MB-231) compared with the normal breast cells (MCF-10A) using the qRT-PCR technique. False-positive DEMs were avoided by comparing the DEMs profile of TNBC and triple positive breast cancer (TPBC) cell line model (BT474) compared with the MCF-10A cells data. In addition, we studied the effect of anticancer phytochemicals on the differential expression of miRNAs and genes in MDA-MB-231 cells. Furthermore, target predictions, functional enrichment and KEGG pathway analysis, mutation and copy number alterations, and overall survival analysis of DEMs in TNBC sample was investigated using standard computational tools. The study identifies first time the association of hsa-miR-1250, has-miR-1273, and has-miR-635 with the TNBC. DEMs showed significant association with the Wnt, ErbB, PI3-Akt and cAMP signaling pathways having clinical implications in TNBC tumorigenesis. The DEMs and hub genes (HOXC6 and ACVR2B) showed survival disadvantages in TNBC patients. In summary, the identified miRNAs and hub genes show important implications in TNBC tumorigenesis and patient survival. We recommend further experimental studies on pathophysiological mechanism of the identified miRNAs and hub genes in TNBC. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.15180297
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.