cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.22725855
title: Dealkenylation of neoandrographolide, a phytochemical from <i>Andrographis paniculata</i> stimulates FXR (Farnesoid X Receptor) and enhances gallstone dissolution

description: FXR (Farnesoid X Receptor) is one of the nuclear receptors expressed in the liver performing a significant role in the maintenance of bile acid concentration. An imbalance of cholesterol and bile acid ratio due to any undefined reason could cause gallstone formation. Hence, this paper aims to screen phytochemicals that could maintain a requisite balance of cholesterol and bile acid by targeting FXR and thereby contributing to the dissolution of gallstone. Nineteen phytochemicals were selected and queried for Pa and Pi in the way2drug online server for hepatoprotective property, cholesterol synthesis and absorption inhibition property, and β-glucuronidase inhibiting activity. Cianidanol, neoandrographolide, cynarine, saponins, and tanins with satisfying stated properties were docked with the screened FXR (PDB ID- 1OSH) using HADDOCK server, followed by pharmacokinetics study utilizing SwissADME tool. Neoandrographolide fits best among the other selected literature-based phytochemicals with minor violation of ‘Brenk’s rule’. The violation was corrected with the removal of an alkene group in the provided ChemDraw space of SwissADME. This Dealkenylated compound was further docked with FXR. The promising response under the static condition of the Dealkenylated compound was analyzed for molecular dynamic simulation at physiological conditions for 100 ns. Dealkenylated Neoandrographolide (DN) exhibited hepatoprotective, cholesterol synthesis and absorption inhibition property, and β-glucuronidase inhibition activity with a superior binding score of −42.6+/-1.5 with FXR. The interaction of the FXR receptor and the DN showed exceptional stability at physiological conditions during MD simulation and fit for the ADME properties, therefore it could be a potent candidate to dissolve gallstones. Communicated by Ramaswamy H. Sarma.
DOI: 10.6084/m9.figshare.22725855.v1
title: Dealkenylation of neoandrographolide, a phytochemical from <i>Andrographis paniculata</i> stimulates FXR (Farnesoid X Receptor) and enhances gallstone dissolution

description: FXR (Farnesoid X Receptor) is one of the nuclear receptors expressed in the liver performing a significant role in the maintenance of bile acid concentration. An imbalance of cholesterol and bile acid ratio due to any undefined reason could cause gallstone formation. Hence, this paper aims to screen phytochemicals that could maintain a requisite balance of cholesterol and bile acid by targeting FXR and thereby contributing to the dissolution of gallstone. Nineteen phytochemicals were selected and queried for Pa and Pi in the way2drug online server for hepatoprotective property, cholesterol synthesis and absorption inhibition property, and β-glucuronidase inhibiting activity. Cianidanol, neoandrographolide, cynarine, saponins, and tanins with satisfying stated properties were docked with the screened FXR (PDB ID- 1OSH) using HADDOCK server, followed by pharmacokinetics study utilizing SwissADME tool. Neoandrographolide fits best among the other selected literature-based phytochemicals with minor violation of ‘Brenk’s rule’. The violation was corrected with the removal of an alkene group in the provided ChemDraw space of SwissADME. This Dealkenylated compound was further docked with FXR. The promising response under the static condition of the Dealkenylated compound was analyzed for molecular dynamic simulation at physiological conditions for 100 ns. Dealkenylated Neoandrographolide (DN) exhibited hepatoprotective, cholesterol synthesis and absorption inhibition property, and β-glucuronidase inhibition activity with a superior binding score of −42.6+/-1.5 with FXR. The interaction of the FXR receptor and the DN showed exceptional stability at physiological conditions during MD simulation and fit for the ADME properties, therefore it could be a potent candidate to dissolve gallstones. Communicated by Ramaswamy H. Sarma.
DOI: 10.6084/m9.figshare.19322579
title: <i>In silico</i> and <i>in vitro</i> studies on inhibitors for SARS-CoV-2 non-structural proteins with dual herbal combination of <i>Withania somnifera</i> with five rasayana herbs

description: Being highly transmissible, severe acute respiratory syndrome coronavirus (SARS-CoV-2) has affected millions of people causing devastating global impact and has also not slowed down even after vaccination. The emerges of new strains has made more concerns than the original one. We need a new therapeutic approach against the disease. Our comprehensive <i>in silico</i> study investigates dual herbal combinatorial methanolic extracts of <i>W. somnifera</i> (W) alone and with <i>P. emblica</i> (P) (W:P/1:4) , <i>T. sinensis</i> (T) (W:T/1:4), <i>B. monnieri</i> (B) (W:B/1:1), <i>O. basilicum</i> (O) (W:O/1:4), <i>A. racemosus</i> (A) (W:A/4:1) for potential four phytochemicals as ligands docked with eight COVID-19 Nonstructural proteins (nsp)—main protease (PDB ID:6LU7), papain-like protease (6WUU), helicase ADP (2XZL), N7-methyltransferase (5C8S), endoribonuclease (6WLC), 2’O-methyltransferase (6WVN), RNA dependent RNA polymerase (6M71), and 3Cprotease (6YNQ) along with Remdesivir and Hydroxychloroquine. Ligands from W:P/1:4 showed remarkable docking score (−9.01 kcal/mol) 6M71-(8E,11E,14E)-eicosa-8,11,14-trienoicacidmethylester (EIS) and (−9.99 kcal/mol) 6YNQ-N-[(E)-[4-[(2-methoxydibenzofuran-3-yl)amino]-4-oxobutan-2-ylidene]amino] 4nitrobenzamide (MET). Further, MD simulations were studied for 100 ns and showed the complexes were flexible, stable in the binding pockets of the receptors, and MM-PBSA analysis determined high binding energy of −129.673 ± 15.284 and −134.594 ± 7.085 for 6M71-EIS (Asn<sup>496</sup>, Lys<sup>577</sup>, Arg<sup>569</sup>) and 6YNQ-MET (Cys<sup>145</sup>, His<sup>41</sup>). Finally, <i>in vitro</i> JURKAT E6.1 cell lines treated with W:P/1:4 and W:O/1:4 methanolic extracts yielded 44.06 and 31.53 ng/mL levels for interferon alpha to counteract an external stimulus by establishing an antiviral state. Thus, nsp is targeted to design effective antiviral drugs for developing an effective therapeutic approach to combat viral RNA synthesis, processing, and suppression of host immunity. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.19459838
title: Computational investigation of aphid odorant receptor structure and binding function

description: Odorant receptors (OR) play a critical role in signal transduction and olfactory recognition in insects. Unfortunately, insect ORs are difficult to express and purify, and limited structural data are available. Computational methods were used to predict models for aphid ORs, and binding interactions with aphid pheromones and other semiochemicals were investigated. Previously functionally characterised ORs from the pea aphid, <i>Acyrthosiphon pisum</i>, ApisOR4 and ApisOR5, were screened against functional ligands. ApisOR5 had a defined binding site, and had predicted interactions with the aphid alarm pheromone, (<i>E)-</i>β<i>-</i>farnesene. ApisOR4 had multiple distinct binding sites and showed broad tuning to multiple odorants. Screening of six other highly conserved ORs showed some interactions and potential enantiomeric discrimination between the aphid sex pheromone components (4a<i>S</i>,7<i>S</i>,7a<i>R</i>)-nepetalactone and (1<i>R</i>,4a<i>S</i>,7<i>S</i>,7a<i>R</i>)-nepetalactol. These results indicate that specific binding sites may be more critical to understanding olfactory activity of ligands and ORs than kinetic data, and greater knowledge of the method of action of ORs is required. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.19459838.v1
title: Computational investigation of aphid odorant receptor structure and binding function

description: Odorant receptors (OR) play a critical role in signal transduction and olfactory recognition in insects. Unfortunately, insect ORs are difficult to express and purify, and limited structural data are available. Computational methods were used to predict models for aphid ORs, and binding interactions with aphid pheromones and other semiochemicals were investigated. Previously functionally characterised ORs from the pea aphid, <i>Acyrthosiphon pisum</i>, ApisOR4 and ApisOR5, were screened against functional ligands. ApisOR5 had a defined binding site, and had predicted interactions with the aphid alarm pheromone, (<i>E)-</i>β<i>-</i>farnesene. ApisOR4 had multiple distinct binding sites and showed broad tuning to multiple odorants. Screening of six other highly conserved ORs showed some interactions and potential enantiomeric discrimination between the aphid sex pheromone components (4a<i>S</i>,7<i>S</i>,7a<i>R</i>)-nepetalactone and (1<i>R</i>,4a<i>S</i>,7<i>S</i>,7a<i>R</i>)-nepetalactol. These results indicate that specific binding sites may be more critical to understanding olfactory activity of ligands and ORs than kinetic data, and greater knowledge of the method of action of ORs is required. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.19322579.v2
title: <i>In silico</i> and <i>in vitro</i> studies on inhibitors for SARS-CoV-2 non-structural proteins with dual herbal combination of <i>Withania somnifera</i> with five rasayana herbs

description: Being highly transmissible, severe acute respiratory syndrome coronavirus (SARS-CoV-2) has affected millions of people causing devastating global impact and has also not slowed down even after vaccination. The emerges of new strains has made more concerns than the original one. We need a new therapeutic approach against the disease. Our comprehensive <i>in silico</i> study investigates dual herbal combinatorial methanolic extracts of <i>W. somnifera</i> (W) alone and with <i>P. emblica</i> (P) (W:P/1:4) , <i>T. sinensis</i> (T) (W:T/1:4), <i>B. monnieri</i> (B) (W:B/1:1), <i>O. basilicum</i> (O) (W:O/1:4), <i>A. racemosus</i> (A) (W:A/4:1) for potential four phytochemicals as ligands docked with eight COVID-19 Nonstructural proteins (nsp)—main protease (PDB ID:6LU7), papain-like protease (6WUU), helicase ADP (2XZL), N7-methyltransferase (5C8S), endoribonuclease (6WLC), 2’O-methyltransferase (6WVN), RNA dependent RNA polymerase (6M71), and 3Cprotease (6YNQ) along with Remdesivir and Hydroxychloroquine. Ligands from W:P/1:4 showed remarkable docking score (−9.01 kcal/mol) 6M71-(8E,11E,14E)-eicosa-8,11,14-trienoicacidmethylester (EIS) and (−9.99 kcal/mol) 6YNQ-N-[(E)-[4-[(2-methoxydibenzofuran-3-yl)amino]-4-oxobutan-2-ylidene]amino] 4nitrobenzamide (MET). Further, MD simulations were studied for 100 ns and showed the complexes were flexible, stable in the binding pockets of the receptors, and MM-PBSA analysis determined high binding energy of −129.673 ± 15.284 and −134.594 ± 7.085 for 6M71-EIS (Asn<sup>496</sup>, Lys<sup>577</sup>, Arg<sup>569</sup>) and 6YNQ-MET (Cys<sup>145</sup>, His<sup>41</sup>). Finally, <i>in vitro</i> JURKAT E6.1 cell lines treated with W:P/1:4 and W:O/1:4 methanolic extracts yielded 44.06 and 31.53 ng/mL levels for interferon alpha to counteract an external stimulus by establishing an antiviral state. Thus, nsp is targeted to design effective antiviral drugs for developing an effective therapeutic approach to combat viral RNA synthesis, processing, and suppression of host immunity. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.19322579.v1
title: <i>In silico</i> and <i>in vitro</i> studies on inhibitors for SARS-CoV-2 non-structural proteins with dual herbal combination of <i>Withania somnifera</i> with five rasayana herbs

description: Being highly transmissible, severe acute respiratory syndrome coronavirus (SARS-CoV-2) has affected millions of people causing devastating global impact and has also not slowed down even after vaccination. The emerges of new strains has made more concerns than the original one. We need a new therapeutic approach against the disease. Our comprehensive <i>in silico</i> study investigates dual herbal combinatorial methanolic extracts of <i>W. somnifera</i> (W) alone and with <i>P. emblica</i> (P) (W:P/1:4) , <i>T. sinensis</i> (T) (W:T/1:4), <i>B. monnieri</i> (B) (W:B/1:1), <i>O. basilicum</i> (O) (W:O/1:4), <i>A. racemosus</i> (A) (W:A/4:1) for potential four phytochemicals as ligands docked with eight COVID-19 Nonstructural proteins (nsp)—main protease (PDB ID:6LU7), papain-like protease (6WUU), helicase ADP (2XZL), N7-methyltransferase (5C8S), endoribonuclease (6WLC), 2’O-methyltransferase (6WVN), RNA dependent RNA polymerase (6M71), and 3Cprotease (6YNQ) along with Remdesivir and Hydroxychloroquine. Ligands from W:P/1:4 showed remarkable docking score (−9.01 kcal/mol) 6M71-(8E,11E,14E)-eicosa-8,11,14-trienoicacidmethylester (EIS) and (−9.99 kcal/mol) 6YNQ-N-[(E)-[4-[(2-methoxydibenzofuran-3-yl)amino]-4-oxobutan-2-ylidene]amino] 4nitrobenzamide (MET). Further, MD simulations were studied for 100 ns and showed the complexes were flexible, stable in the binding pockets of the receptors, and MM-PBSA analysis determined high binding energy of −129.673 ± 15.284 and −134.594 ± 7.085 for 6M71-EIS (Asn<sup>496</sup>, Lys<sup>577</sup>, Arg<sup>569</sup>) and 6YNQ-MET (Cys<sup>145</sup>, His<sup>41</sup>). Finally, <i>in vitro</i> JURKAT E6.1 cell lines treated with W:P/1:4 and W:O/1:4 methanolic extracts yielded 44.06 and 31.53 ng/mL levels for interferon alpha to counteract an external stimulus by establishing an antiviral state. Thus, nsp is targeted to design effective antiviral drugs for developing an effective therapeutic approach to combat viral RNA synthesis, processing, and suppression of host immunity. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.22725858
title: Neem and Turmeric in the management of Covid Associated Mucormycosis (CAM) derived through network pharmacology

description: Mucormycosis or ‘Black Fungus’ has been known to target immunocompromised individuals even before the emergence of COVID-19. Nevertheless, the present circumstances provide the best opening for Covid Associated Mucormycosis (CAM), as the global pandemic is engulfing a large part of human population making them immunocompromised. This drastic increase in Mucormycosis infections has to be addressed as early as possible. There is a growing tendency of relying upon herbal drugs that have minimal side effects and does not compromise our immune system. Recently, the concept of network pharmacology has grabbed the attention of modern science, especially advanced medical sciences. This is a new discipline that can use computational power to systematically catalogue the molecular interactions between botanical formulations and the human body. In this study, Neem and Turmeric was considered as the target plants and an attempt was made to reveal various aspects through which phytocompounds derived from them may effectively manage CAM menace. We have taken a step-by-step approach for identifying the target proteins and ligands associated with Mucormycosis treatment. Functional network analysis and Molecular docking approaches were applied to validate our findings. Quercetin derived from both Neem and Turmeric was found to be one of the main phytocompounds working against Mucormycosis. Along with that, Caffeic acid, Curcumin, Kaempferol, Tetrahydrocurcumin and Myricetin also play a pivotal role in fighting against Black-Fungus. A thorough analysis of our result suggested a triple-front attack on the fungal pathogens and the approaches are necrosis inhibition, iron chelation and immuno-boosting. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.22725858.v1
title: Neem and Turmeric in the management of Covid Associated Mucormycosis (CAM) derived through network pharmacology

description: Mucormycosis or ‘Black Fungus’ has been known to target immunocompromised individuals even before the emergence of COVID-19. Nevertheless, the present circumstances provide the best opening for Covid Associated Mucormycosis (CAM), as the global pandemic is engulfing a large part of human population making them immunocompromised. This drastic increase in Mucormycosis infections has to be addressed as early as possible. There is a growing tendency of relying upon herbal drugs that have minimal side effects and does not compromise our immune system. Recently, the concept of network pharmacology has grabbed the attention of modern science, especially advanced medical sciences. This is a new discipline that can use computational power to systematically catalogue the molecular interactions between botanical formulations and the human body. In this study, Neem and Turmeric was considered as the target plants and an attempt was made to reveal various aspects through which phytocompounds derived from them may effectively manage CAM menace. We have taken a step-by-step approach for identifying the target proteins and ligands associated with Mucormycosis treatment. Functional network analysis and Molecular docking approaches were applied to validate our findings. Quercetin derived from both Neem and Turmeric was found to be one of the main phytocompounds working against Mucormycosis. Along with that, Caffeic acid, Curcumin, Kaempferol, Tetrahydrocurcumin and Myricetin also play a pivotal role in fighting against Black-Fungus. A thorough analysis of our result suggested a triple-front attack on the fungal pathogens and the approaches are necrosis inhibition, iron chelation and immuno-boosting. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.19369263
title: Atomic level and structural understanding of natural ligands inhibiting <i>Helicobacter pylori</i> peptide deformylase through ligand and receptor based screening, SIFT, molecular dynamics and DFT – a structural computational approach

description: <i>Helicobacter pylori</i> is a Gram-negative microaerophilic gastric pathogen, responsible for the cause of peptic ulcer around half of the global population. Although several antibiotics and combination therapies have been employed for <i>H. pylori</i>-related gastric ulcer and cancer regiments, identifying potent inhibitors for specific targets of this bacterium will help assessing better treatment periodicity and methods to eradicate <i>H. pylori</i>. Herein, 1,000,000 natural compounds were virtually screened against <i>Helicobacter pylori</i> Peptide deformylase (HpPDF). Pharmacophore hypotheses were created using ligand and receptor-based pharmacophore modeling of GLIDE. Stringent HTVS and IFD docking protocol of GLIDE predicted leads with stable intermolecular bonds and scores. Molecular dynamics simulation of HpPDF was carried out for 100 ns using GROMACS. Hits ZINC00225109 and ZINC44896875 came up with a glide score of −9.967 kcal/mol and −12.114 kcal/mol whereas; reference compound actinonin produced a glide score of −9.730 kcal/mol. Binding energy values of these hits revealed the involvement of significant Van der Waals and Coulomb forces and the deduction of lipophilic forces that portray the deep hydrophobic residues in the S1pocket of <i>H. pylori</i>. The DFT analysis established the electron density-based features of the molecules and observed that the results correlate with intermolecular docking interactions. Analysis of the MD trajectories revealed the crucial residues involved in HpPDF – ligand binding and the conformational changes in the receptor. We have identified and deciphered the crucial features necessary for the potent ligand binding at catalytic site of HpPDF. The resulting ZINC natural compound hits from the study could be further employed for potent drug development. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.19369263.v1
title: Atomic level and structural understanding of natural ligands inhibiting <i>Helicobacter pylori</i> peptide deformylase through ligand and receptor based screening, SIFT, molecular dynamics and DFT – a structural computational approach

description: <i>Helicobacter pylori</i> is a Gram-negative microaerophilic gastric pathogen, responsible for the cause of peptic ulcer around half of the global population. Although several antibiotics and combination therapies have been employed for <i>H. pylori</i>-related gastric ulcer and cancer regiments, identifying potent inhibitors for specific targets of this bacterium will help assessing better treatment periodicity and methods to eradicate <i>H. pylori</i>. Herein, 1,000,000 natural compounds were virtually screened against <i>Helicobacter pylori</i> Peptide deformylase (HpPDF). Pharmacophore hypotheses were created using ligand and receptor-based pharmacophore modeling of GLIDE. Stringent HTVS and IFD docking protocol of GLIDE predicted leads with stable intermolecular bonds and scores. Molecular dynamics simulation of HpPDF was carried out for 100 ns using GROMACS. Hits ZINC00225109 and ZINC44896875 came up with a glide score of −9.967 kcal/mol and −12.114 kcal/mol whereas; reference compound actinonin produced a glide score of −9.730 kcal/mol. Binding energy values of these hits revealed the involvement of significant Van der Waals and Coulomb forces and the deduction of lipophilic forces that portray the deep hydrophobic residues in the S1pocket of <i>H. pylori</i>. The DFT analysis established the electron density-based features of the molecules and observed that the results correlate with intermolecular docking interactions. Analysis of the MD trajectories revealed the crucial residues involved in HpPDF – ligand binding and the conformational changes in the receptor. We have identified and deciphered the crucial features necessary for the potent ligand binding at catalytic site of HpPDF. The resulting ZINC natural compound hits from the study could be further employed for potent drug development. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.19328871.v1
title: An <i>in silico</i> discovery of potential 3CL protease inhibitors of SARS-CoV-2 based upon inactivation of the cysteine 145-Histidine 41 catalytic dyad

description: Coronavirus disease 19 (COVID19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, several countries are at risk of the pandemic caused by this virus. In the absence of any vaccine or virus-specific antiviral treatments, the need is to fast track search for potential drug candidates to combat the virus. Though there are known drugs that are being repurposed to fight against the SARS-CoV-2, there is a requirement for the virus-specific drugs at the earliest. One of the main drug targets of SARS-CoV-2 is an essential non-structural protein, 3CL protease, critical for the life cycle of the virus. We have used molecular docking studies to screen a chemically diverse set of small molecules to identify potential drug candidates to target this protein. Of the 22,630 molecules from varied small molecule libraries, based on the binding affinities and physicochemical properties, we finalized 30 molecules to be potential drug candidates. Eight of these molecules bind in a manner allowing for the scope of a nearly orthogonal backside nucleophilic attack on their suitably placed electrophilic carbonyl groups by the thiol group of cysteine residue 145, while remaining inside a 4 Ǻ distance range. It is interesting since carbonyl groups are known to be attacked in a similar fashion by external nucleophiles and can be relevant when considering these molecules as potential mechanism-based irreversible inhibitors of the 3CL<sup>Pro</sup>. Further, ADMET analysis and Molecular dynamics simulations and available bioactive assays led to the identification of three molecules with high potential to be explored as drug candidates/lead molecules to target 3CL<sup>Pro</sup> of SARS-CoV-2. Communicated by Ramaswamy H. Sarma