cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.14778533.v1
title: <i>Combretum lanceolatum</i> extract reverses anxiety and seizure behavior in adult zebrafish through GABAergic neurotransmission: an <i>in vivo and in silico</i> study

description: <i>Combretaceae</i> are reported in the literature for presenting neuroprotective and anxiolytic effects in animal models. <i>Combretum lanceolatum Pohl.</i> has few scientific reports on its pharmacological effects. The aim of this study was to evaluate the anxiolytic and anticonvulsant effects of the ethanol extract from the leaves of <i>C. lanceolatum Pohl.</i> (EtFoCl) and its possible mechanism of GABAergic action in adult zebrafish. EtFoCl was subjected to determination of the total phenol concentration, identification of phytochemical flavonoids by HPLC and <i>in vitro</i> antioxidant activity test, open field test and 96-hour acute toxicity in zebrafish. Anxiolytic doses were tested for pentylenetetrazole-induced seizures in adult zebrafish. To study the mechanisms of action, molecular docking simulations were performed between the main phytochemicals and the GABAA receptor (anxiolytic activity) and carbonic anhydrase II (anticonvulsant). The non-toxic doses that caused motor impairment were assessed in acute and chronic anxiety using the light and dark test. EtFoCl had altered the animals’ locomotion, presenting an effect similar to the anxiolytic and anticonvulsant. These effects were prevented with flumazenil (GABAA antagonist). The phytochemicals homoorientin and quercetin-3-O-galactoside coupling in a region close to that of the inhibitor diazepam (GABAA receptor). Regarding the anticonvulsant mechanism, Homoorientina and Isovitexina were identified as the most favorable for the complex form with the carbonic anhydrase enzyme. <i>C. lanceolatum</i> has pharmacological potential for the treatment of acute and chronic anxiety and seizures, which can be partially explained by an interaction with the GABAA receptor. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.14822889.v1
title: Integrated docking and enhanced sampling-based selection of repurposing drugs for SARS-CoV-2 by targeting host dependent factors

description: Since the onset of global pandemic, the most focused research currently in progress is the development of potential drug candidates and clinical trials of existing FDA approved drugs for other relevant diseases, in order to repurpose them for the COVID-19. At the same time, several high throughput screenings of drugs have been reported to inhibit the viral components during the early course of infection but with little proven efficacies. Here, we investigate the drug repurposing strategies to counteract the coronavirus infection which involves several potential targetable host proteins involved in viral replication and disease progression. We report the high throughput analysis of literature-derived repurposing drug candidates that can be used to target the genetic regulators known to interact with viral proteins based on experimental and interactome studies. In this work we have performed integrated molecular docking followed by molecular dynamics (MD) simulations and free energy calculations through an expedite in silico process where the number of screened candidates reduces sequentially at every step based on physicochemical interactions. We elucidate that in addition to the pre-clinical and FDA approved drugs that targets specific regulatory proteins, a range of chemical compounds (Nafamostat, Chloramphenicol, Ponatinib) binds to the other gene transcription and translation regulatory proteins with higher affinity and may harbour potential for therapeutic uses. There is a rapid growing interest in the development of combination therapy for COVID-19 to target multiple enzymes/pathways. Our in silico approach would be useful in generating leads for experimental screening for rapid drug repurposing against SARS-CoV-2 interacting host proteins. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.14810615.v1
title: Mechanistic insights into 5-lipoxygenase inhibition by pyocyanin: a molecular docking and molecular dynamics study

description: Pyocyanin, a redox-active phenazine pigment produced by <i>Pseudomonas aeruginosa</i>, inhibits 5-lipoxygenase (5-LOX) activity. However, whether pyocyanin can directly block the enzymatic activity by binding at the active site still remains a question because of its ability to produce superoxide radicals and H<sub>2</sub>O<sub>2</sub>. With the objective of characterizing this mechanism, we carried out molecular docking and molecular dynamics simulations and performed Molecular Mechanics Poisson-Boltzmann surface area (MMPBSA) binding energy studies. The results of the study revealed that pyocyanin is dynamically stable at the active site of 5-LOX and its MMPBSA binding energy (−84.720 kJ/mol) is comparable to that of the 5-LOX standard inhibitor zileuton (−72.729 kJ/mol). Similar studies using three other phenazine derivatives − 1-hydroxyphenazine, phenazine-1-carboxylic acid and phenazine-1-carboxamide – also showed encouraging results. In light of this evidence, we postulate as a proof of concept that pyocyanin and these phenazine derivatives have the potential to inhibit 5-LOX activity by directly binding at the active site and blocking enzymatic catalysis of the substrate. Considering the potential of 5-LOX inhibitors in inflammatory diseases such as asthma and rheumatoid arthritis, the findings of this study open up the exploration of phenazine derivatives in structure-based drug design against 5-LOX. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.15082399.v1
title: Modeling the structure and reactivity landscapes of a pyrazole-ammonium ionic derivative using wavefunction-dependent characteristics and screening for potential anti-inflammatory activity

description: Spectroscopic investigations of 1-phenyl −2,3-dimethyl-5-oxo-1,2-dihydro-1<i>H</i>-pyrazol-4-ammonium 2[(2-carboxyphenyl) disulfanyl]benzoate (PACB) reported experimentally and theoretically. NH-O interaction is observed and there is a very large downshift for NH-O stretching frequency. Reactive sites are identified from the chemical and electronic properties. For PACB the maximum repulsion was around H33, H55 and H57 atom. LOL shows red regions between C-C and blue around C atoms are surrounded by a delocalized electron cloud. The red ring is a hallmark of electron density depletion from the NCI plot due to electrostatic repulsion and its existences suggests that coordination sphere for PACB is minimally strained around the central ion. Atomic contact energy values and high score of the docking results obtained propose that, PACB may have inhibitory properties and have a significant function in pharmacological chemistry. Molecular dynamics simulation was performed to validate the stability of the title compound with the Bovine thrombin-activatable fibrinolysis inhibitor protein. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.14810615
title: Mechanistic insights into 5-lipoxygenase inhibition by pyocyanin: a molecular docking and molecular dynamics study

description: Pyocyanin, a redox-active phenazine pigment produced by <i>Pseudomonas aeruginosa</i>, inhibits 5-lipoxygenase (5-LOX) activity. However, whether pyocyanin can directly block the enzymatic activity by binding at the active site still remains a question because of its ability to produce superoxide radicals and H<sub>2</sub>O<sub>2</sub>. With the objective of characterizing this mechanism, we carried out molecular docking and molecular dynamics simulations and performed Molecular Mechanics Poisson-Boltzmann surface area (MMPBSA) binding energy studies. The results of the study revealed that pyocyanin is dynamically stable at the active site of 5-LOX and its MMPBSA binding energy (−84.720 kJ/mol) is comparable to that of the 5-LOX standard inhibitor zileuton (−72.729 kJ/mol). Similar studies using three other phenazine derivatives − 1-hydroxyphenazine, phenazine-1-carboxylic acid and phenazine-1-carboxamide – also showed encouraging results. In light of this evidence, we postulate as a proof of concept that pyocyanin and these phenazine derivatives have the potential to inhibit 5-LOX activity by directly binding at the active site and blocking enzymatic catalysis of the substrate. Considering the potential of 5-LOX inhibitors in inflammatory diseases such as asthma and rheumatoid arthritis, the findings of this study open up the exploration of phenazine derivatives in structure-based drug design against 5-LOX. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.15082399
title: Modeling the structure and reactivity landscapes of a pyrazole-ammonium ionic derivative using wavefunction-dependent characteristics and screening for potential anti-inflammatory activity

description: Spectroscopic investigations of 1-phenyl −2,3-dimethyl-5-oxo-1,2-dihydro-1<i>H</i>-pyrazol-4-ammonium 2[(2-carboxyphenyl) disulfanyl]benzoate (PACB) reported experimentally and theoretically. NH-O interaction is observed and there is a very large downshift for NH-O stretching frequency. Reactive sites are identified from the chemical and electronic properties. For PACB the maximum repulsion was around H33, H55 and H57 atom. LOL shows red regions between C-C and blue around C atoms are surrounded by a delocalized electron cloud. The red ring is a hallmark of electron density depletion from the NCI plot due to electrostatic repulsion and its existences suggests that coordination sphere for PACB is minimally strained around the central ion. Atomic contact energy values and high score of the docking results obtained propose that, PACB may have inhibitory properties and have a significant function in pharmacological chemistry. Molecular dynamics simulation was performed to validate the stability of the title compound with the Bovine thrombin-activatable fibrinolysis inhibitor protein. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.14920749.v1
title: Comparative analysis of SARS-CoV-2 envelope viroporin mutations from COVID-19 deceased and surviving patients revealed implications on its ion-channel activities and correlation with patient mortality

description: One major obstacle in designing a successful therapeutic regimen to combat COVID-19 pandemic is the frequent occurrence of mutations in the SARS-CoV-2 resulting in patient to patient variations. Out of the four structural proteins of SARS-CoV-2 namely, spike, envelope, nucleocapsid and membrane, envelope protein governs the virus pathogenicity and induction of acute-respiratory-distress-syndrome which is the major cause of death in COVID-19 patients. These effects are facilitated by the viroporin (ion-channel) like activities of the envelope protein. Our current work reports metagenomic analysis of envelope protein at the amino acid sequence level through mining all the available SARS-CoV-2 genomes from the GISAID and <i>coronapp</i> servers. We found majority of mutations in envelope protein were localized at or near PDZ binding motif. Our analysis also demonstrates that the acquired mutations might have important implications on its structure and ion-channel activity. A statistical correlation between specific mutations (e.g. F4F, R69I, P71L, L73F) with patient mortalities were also observed, based on the patient data available for 18,691 SARS-CoV-2-genomes in the GISAID database till 30 April 2021. Albeit, whether these mutations exist as the cause or the effect of co-infections and/or co-morbid disorders within COVID-19 patients is still unclear. Moreover, most of the current vaccine and therapeutic interventions are revolving around spike protein. However, emphasizing on envelope protein’s (1) conserved epitopes, (2) pathogenicity attenuating mutations, and (3) mutations present in the deceased patients, as reported in our present study, new directions to the ongoing efforts of therapeutic developments against COVID-19 can be achieved by targeting envelope viroporin. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.14920749
title: Comparative analysis of SARS-CoV-2 envelope viroporin mutations from COVID-19 deceased and surviving patients revealed implications on its ion-channel activities and correlation with patient mortality

description: One major obstacle in designing a successful therapeutic regimen to combat COVID-19 pandemic is the frequent occurrence of mutations in the SARS-CoV-2 resulting in patient to patient variations. Out of the four structural proteins of SARS-CoV-2 namely, spike, envelope, nucleocapsid and membrane, envelope protein governs the virus pathogenicity and induction of acute-respiratory-distress-syndrome which is the major cause of death in COVID-19 patients. These effects are facilitated by the viroporin (ion-channel) like activities of the envelope protein. Our current work reports metagenomic analysis of envelope protein at the amino acid sequence level through mining all the available SARS-CoV-2 genomes from the GISAID and <i>coronapp</i> servers. We found majority of mutations in envelope protein were localized at or near PDZ binding motif. Our analysis also demonstrates that the acquired mutations might have important implications on its structure and ion-channel activity. A statistical correlation between specific mutations (e.g. F4F, R69I, P71L, L73F) with patient mortalities were also observed, based on the patient data available for 18,691 SARS-CoV-2-genomes in the GISAID database till 30 April 2021. Albeit, whether these mutations exist as the cause or the effect of co-infections and/or co-morbid disorders within COVID-19 patients is still unclear. Moreover, most of the current vaccine and therapeutic interventions are revolving around spike protein. However, emphasizing on envelope protein’s (1) conserved epitopes, (2) pathogenicity attenuating mutations, and (3) mutations present in the deceased patients, as reported in our present study, new directions to the ongoing efforts of therapeutic developments against COVID-19 can be achieved by targeting envelope viroporin. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.14914905.v1
title: Discovery of novel ALK2 inhibitors of pyrazolo-pyrimidines: A computational study

description: ALK2 is a serine/threonine kinase, involved in different signaling pathways and associated with cell proliferation and differentiation. The present study includes development of pharmacophore, 3-D QSAR, docking and virtual screening studies on 30 different pyrazolo[1,5-a]pyrimidine derivatives. The pharmacophore study provides ARRR_2 hypothesis with four different features essential for ALK2 kinase inhibitory activity. The 3 D-QSAR study determined the statistically significant model by using partial least-square regression (PLS) method with <i>R</i><sup>2</sup> value of 0.9711 and <i>Q</i><sup>2</sup> value of 0.6846. Validation of 3 D-QSAR has been performed by LOO cross-validation method where with R<sup>2</sup>CV value of 0.56. The virtual screening study on ZINC database provides compounds such as ZINC66091638, ZINC43524105, ZINC19458227 and ZINC72441013 involved good binding interactions (docking scores −8.91, −7.40, −8.43, and −9.47, respectively) with ALK2 kinase (PDB ID: 3Q4U). The docking study of pyrazolo-pyrimidines derivatives found potent compounds, 7i, 13r, 13d, and 21 with docking scores −9.83, −9.75, −9.76, and −9.75, respectively. The important interactions with amino acid residues were HID 286, ASN341. ADME properties further assist to provide important structural features of ALK2 kinase. The present study may be help to medicinal scientists in the direction to develop potent inhibitors against ALK2 kinase. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.14914905
title: Discovery of novel ALK2 inhibitors of pyrazolo-pyrimidines: A computational study

description: ALK2 is a serine/threonine kinase, involved in different signaling pathways and associated with cell proliferation and differentiation. The present study includes development of pharmacophore, 3-D QSAR, docking and virtual screening studies on 30 different pyrazolo[1,5-a]pyrimidine derivatives. The pharmacophore study provides ARRR_2 hypothesis with four different features essential for ALK2 kinase inhibitory activity. The 3 D-QSAR study determined the statistically significant model by using partial least-square regression (PLS) method with <i>R</i><sup>2</sup> value of 0.9711 and <i>Q</i><sup>2</sup> value of 0.6846. Validation of 3 D-QSAR has been performed by LOO cross-validation method where with R<sup>2</sup>CV value of 0.56. The virtual screening study on ZINC database provides compounds such as ZINC66091638, ZINC43524105, ZINC19458227 and ZINC72441013 involved good binding interactions (docking scores −8.91, −7.40, −8.43, and −9.47, respectively) with ALK2 kinase (PDB ID: 3Q4U). The docking study of pyrazolo-pyrimidines derivatives found potent compounds, 7i, 13r, 13d, and 21 with docking scores −9.83, −9.75, −9.76, and −9.75, respectively. The important interactions with amino acid residues were HID 286, ASN341. ADME properties further assist to provide important structural features of ALK2 kinase. The present study may be help to medicinal scientists in the direction to develop potent inhibitors against ALK2 kinase. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.14914985.v1
title: <i>In silico</i> identification of antidiabetic target for phytochemicals of <i>A. marmelos</i> and mechanistic insights by molecular dynamics simulations

description: The leaves and fruits of <i>Aegle marmelos</i> (L.) have antidiabetic activity. However, the mode of action and molecules having antidiabetic activity are not known. Hence, we conducted molecular docking of phytochemicals with various molecular antidiabetic targets to find the same. Docking prioritized Dipeptidyl peptidase-4 (DPP-4) as the main target for phytochemicals of <i>Aegle marmelos</i>. DPP-4 inactivates intestinal peptides, glucagon-like peptide-1 (GLP-1), and Gastric inhibitory polypeptide (GIP). GLP-1 and GIP stimulate a decline in blood glucose levels, but DPP-4 inhibits their functions resulting high level of glucose. Hence inhibiting the activity of DPP-4 is a well-known strategy to treat Type 2 diabetes. Therefore, to find a mechanism that may be involved to act as a natural inhibitor of DPP-4, we screened five phytochemicals out of seventy-three based on Virtual Screening, ADMET Drug-likeness analysis, and PAINS filtering. Further, all five phytochemicals, i.e. Aegeline, Citral, Marmesinin, Auraptene, β-Bisabolene, and reference compound subjected MDS for analyzing the stability of docked complexes to assess the fluctuation and conformational changes during protein-ligand interaction. The values of RMSD, RG, RMSF, SASA, and Gibbs energy revealed the good stability of these phytochemicals in the active site pocket of DPP-4 in comparison to reference. Additionally, we have done the pharmacophore analysis, which revealed many common pharmacophore features between screened phytochemicals of <i>A. marmelos</i> and reference molecule. Our results show that these phytochemicals are potential antidiabetic candidates and can be further modified and evaluated to develop more effective antidiabetic drugs against DPP-4 to treat Type 2 Diabetes. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.15015539
title: Investigation of reactive properties, adsorption on fullerene, DFT, molecular dynamics simulation of an anthracene derivative targeting dihydrofolate reductase and human dUTPase

description: Anthracenes are aromatic compounds with flexible structure and reactivity which are of great interest to theoretical and experimental chemists. Theoretical investigations of 1,4-dihydroxy-5,8-bis[2-(2-hydroxyethylamino)ethylamino]anthracene-9,10-dione (Mitoxantrone) (DDEA) based on density functional theory, molecular dynamics and adsorption on fullerene are reported in the present research. The suitable situation for adsorption with fullerene (C60) is the cyclohex-2-ene-1,4-dione ring of DDEA. Selected quantum-molecular descriptors have been calculated to predict the most reactive sites of the DDEA molecule. Interactions of DDEA with water have been studied using MD simulations. MD simulations were also used to study solubility parameter, a significant quantity for the development of pharmaceutical formulations. The affinity of DDEA on human dihydrofolate reductase and deoxyuridine triphosphatase enzymes was investigated by MD simulation of the protein–ligand complex obtained by molecular docking study. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.15015539.v1
title: Investigation of reactive properties, adsorption on fullerene, DFT, molecular dynamics simulation of an anthracene derivative targeting dihydrofolate reductase and human dUTPase

description: Anthracenes are aromatic compounds with flexible structure and reactivity which are of great interest to theoretical and experimental chemists. Theoretical investigations of 1,4-dihydroxy-5,8-bis[2-(2-hydroxyethylamino)ethylamino]anthracene-9,10-dione (Mitoxantrone) (DDEA) based on density functional theory, molecular dynamics and adsorption on fullerene are reported in the present research. The suitable situation for adsorption with fullerene (C60) is the cyclohex-2-ene-1,4-dione ring of DDEA. Selected quantum-molecular descriptors have been calculated to predict the most reactive sites of the DDEA molecule. Interactions of DDEA with water have been studied using MD simulations. MD simulations were also used to study solubility parameter, a significant quantity for the development of pharmaceutical formulations. The affinity of DDEA on human dihydrofolate reductase and deoxyuridine triphosphatase enzymes was investigated by MD simulation of the protein–ligand complex obtained by molecular docking study. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.15138068
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