cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.14827738
title: Structural basis for the binding of a selective inverse agonist AF64394 with the human G-protein coupled receptor 3 (GPR3)

description: The orphan class A G-protein coupled receptor 3 (GPR3) is highly expressed in brain and linked with various neuronal functions, and therefore, expected to play a vital role in the progression of Alzheimer’s disease. In view of the lack of its experimental structure, we describe herein the three-dimensional structure and conformational dynamics of GPR3 complexed with the inverse agonist AF64394. The GPR3 model was predicted using the Iterative Threading ASSEmbly Refinement (I-TASSER) method. The Induced Fit Docking predicted two unique poses, Pose 1 and Pose 2, for AF64394, and then, molecular dynamics (MD) simulations followed by binding free-energy calculation revealed the Pose 1 as a very stable pose with the least fluctuation during the MD simulation while the Pose 2 underwent a significant fluctuation. The [1,2,4]triazolo[1,5-a]pyrimidine core was engaged in multiple hydrogen bonds (H-bonds), such as a water-mediated H-bond between the triazole nitrogen and T31, two direct H-bonds between the protonated triazole-ring nitrogen and V186 and T279, a direct H-bond between the secondary amine and V187. The phenyl substituent of AF64394 exhibited aromatic π-π stacking interactions with F97, F101, W43 and Y280. AF64394 showed a direct interaction with E28 and polar interactions with H96, T31 and T279. Throughout the MD simulation, the toggle switch residues, F120 and W260, remained in close contact, indicating that the GPR3 conformation represented an inactive state. The 4-(3-chloro-5-isopropoxyphenethyl) group resided near to the toggle switch residues. The insights gained here are expected to be useful in the structure-based design of new ligands targeting GPR3 modulation. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.14778611
title: Elucidation of the inhibitory activity of plant-derived SARS-CoV inhibitors and their potential as SARS-CoV-2 inhibitors

description: Several drugs are now being tested as possible therapies due to the necessity of treating SARS-CoV-2 infection. Although approved vaccines bring much hope, a vaccination program covering the entire global population will take a very long time, making the development of effective antiviral drugs an effective solution for the immediate treatment of this dangerous infection. Previous studies found that three natural compounds, namely, tannic acid, 3-isotheaflavin-3-gallate and theaflavin-3,3-digallate, are effective proteinase (3CL<sup>pro</sup>) inhibitors of SARS-CoV (IC<sub>50</sub> &lt;10 µM). Based on this information and due to the high sequence identity between SARS-CoV and SARS-CoV-2 3CL<sup>pro</sup>, these three compounds could be candidate inhibitors of SARS-CoV-2 3CL<sup>pro</sup>. This paper explores the structural and energetic features that guided the molecular recognition of these three compounds for dimeric SARS-CoV-2 and SARS-CoV 3CL<sup>pro</sup>, the functional state of this enzyme, using docking and MD simulations with the molecular mechanics-generalized-born surface area (MMGBSA) approach. Energetic analysis demonstrated that the three compounds reached good affinities in both systems in the following order: tannic acid &gt; 3-isotheaflavin-3-gallate &gt; theaflavin-3,3-digallate. This tendency is in line with that experimentally reported between these ligands and SARS-CoV 3CL<sup>pro</sup>. Therefore, tannic acid may have clinical usefulness against COVID-19 by acting as a potent inhibitor of SARS-CoV-2 3CL<sup>pro</sup>. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.14778611.v1
title: Elucidation of the inhibitory activity of plant-derived SARS-CoV inhibitors and their potential as SARS-CoV-2 inhibitors

description: Several drugs are now being tested as possible therapies due to the necessity of treating SARS-CoV-2 infection. Although approved vaccines bring much hope, a vaccination program covering the entire global population will take a very long time, making the development of effective antiviral drugs an effective solution for the immediate treatment of this dangerous infection. Previous studies found that three natural compounds, namely, tannic acid, 3-isotheaflavin-3-gallate and theaflavin-3,3-digallate, are effective proteinase (3CL<sup>pro</sup>) inhibitors of SARS-CoV (IC<sub>50</sub> &lt;10 µM). Based on this information and due to the high sequence identity between SARS-CoV and SARS-CoV-2 3CL<sup>pro</sup>, these three compounds could be candidate inhibitors of SARS-CoV-2 3CL<sup>pro</sup>. This paper explores the structural and energetic features that guided the molecular recognition of these three compounds for dimeric SARS-CoV-2 and SARS-CoV 3CL<sup>pro</sup>, the functional state of this enzyme, using docking and MD simulations with the molecular mechanics-generalized-born surface area (MMGBSA) approach. Energetic analysis demonstrated that the three compounds reached good affinities in both systems in the following order: tannic acid &gt; 3-isotheaflavin-3-gallate &gt; theaflavin-3,3-digallate. This tendency is in line with that experimentally reported between these ligands and SARS-CoV 3CL<sup>pro</sup>. Therefore, tannic acid may have clinical usefulness against COVID-19 by acting as a potent inhibitor of SARS-CoV-2 3CL<sup>pro</sup>. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.14716869.v1
title: Chemical profiling, cytotoxic activities through apoptosis induction in MCF-7 cells and molecular docking of <i>Phyllostachys heterocycla</i> bark nonpolar extract

description: The chemical constituents of the nonpolar fractions of the bamboo shoot skin <i>Phyllostachys heterocycla</i> were extensively studied. The phytochemical study was divided into two parts: the first deals with isolation of the chemical constituents using different chromatographic techniques that resulted in isolation of four compounds. The chemical structures of the pure isolated compounds were elucidated using different spectroscopic data. The second part deals with identification of the rest of the constituents using the GC technique. Additionally, both crude extract and the pure isolated compounds were investigated for cytotoxic activity. One of the isolated compounds; namely glyceryl 1-monopalmitate showed highly promising effect against the MCF-7 cells with (IC<sub>50</sub> = 19.78 µM) compared to 5-FU (26.98 µM), and it remarkably stimulated apoptotic breast cancer cell death with 31.6-fold (16.13% compared to 0.51 for the control) at pre-G1 and G2/M-phase cell cycle arrest and blocked the progression of MCF-7 cells. Moreover, the identified compounds especially <b>1</b> were found to have high binding affinity towards both TPK and VEGFR-2 through the molecular docking studies which highlight its mode of action. HighlightsChemical profiling of <i>Phyllostachys heterocycla</i> bark nonpolar extract was fully identified.Glyceryl 1-monopalmitate showed highly promising effect against the MCF-7 cells with (IC<sub>50</sub> = 19.78 µM) compared to 5-FU (26.98 µM).Glyceryl 1-monopalmitate significantly stimulated apoptotic breast cancer cell death with 31.6-fold by arresting cell cycle at G2/M and preG1 phases.Molecular docking simulation showed good binding affinities towards TPK and VEGFR-2 proteins. Chemical profiling of <i>Phyllostachys heterocycla</i> bark nonpolar extract was fully identified. Glyceryl 1-monopalmitate showed highly promising effect against the MCF-7 cells with (IC<sub>50</sub> = 19.78 µM) compared to 5-FU (26.98 µM). Glyceryl 1-monopalmitate significantly stimulated apoptotic breast cancer cell death with 31.6-fold by arresting cell cycle at G2/M and preG1 phases. Molecular docking simulation showed good binding affinities towards TPK and VEGFR-2 proteins. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.14882969
title: Molecular dynamics simulations provide structural insight into binding of cyclic dinucleotides to human STING protein

description: Human stimulator of interferon genes (<i>h</i>STING) is a signaling adaptor protein that triggers innate immune system by response to cytosolic DNA and second messenger cyclic dinucleotides (CDNs). Natural CDNs contain purine nucleobase with different phosphodiester linkage types (3′-3′, 2′-2′ or mixed 2′-3′-linkages) and exhibit different binding affinity towards <i>h</i>STING, ranging from micromolar to nanomolar. High-affinity CDNs are considered as suitable candidates for treatment of chronic hepatitis B and cancer. We have used molecular dynamics simulations to investigate dynamical aspects of binding of natural CDNs (specifically, 2'-2'-cGAMP, 2'-3'-cGAMP, 3'-3'-cGAMP, 3'-3'-c-di-AMP, and 3'-3'-c-di-GMP) with <i>h</i>STING<i><sup>wt</sup></i> protein. Our results revealed that CDN/<i>h</i>STING<i><sup>wt</sup></i> interactions are controlled by the balance between fluctuations (conformational changes) in the CDN ligand and the protein dynamics. Binding of different CDNs induces different degrees of conformational/dynamics changes in <i>h</i>STING<i><sup>wt</sup></i> ligand binding cavity, especially in α<sub>1</sub>-helices, the so-called lid region and α<sub>2</sub>-tails. The ligand residence time in <i>h</i>STING<i><sup>wt</sup></i> protein pocket depends on different contribution of R232 and R238 residues interacting with oxygen atoms of phosphodiester groups in ligand, water distribution around interacting charged centers (in protein residues and ligand) and structural stability of closed conformation state of <i>h</i>STING<i><sup>wt</sup></i> protein. These findings may perhaps guide design of new compounds modulating <i>h</i>STING activity. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.14716869
title: Chemical profiling, cytotoxic activities through apoptosis induction in MCF-7 cells and molecular docking of <i>Phyllostachys heterocycla</i> bark nonpolar extract

description: The chemical constituents of the nonpolar fractions of the bamboo shoot skin <i>Phyllostachys heterocycla</i> were extensively studied. The phytochemical study was divided into two parts: the first deals with isolation of the chemical constituents using different chromatographic techniques that resulted in isolation of four compounds. The chemical structures of the pure isolated compounds were elucidated using different spectroscopic data. The second part deals with identification of the rest of the constituents using the GC technique. Additionally, both crude extract and the pure isolated compounds were investigated for cytotoxic activity. One of the isolated compounds; namely glyceryl 1-monopalmitate showed highly promising effect against the MCF-7 cells with (IC<sub>50</sub> = 19.78 µM) compared to 5-FU (26.98 µM), and it remarkably stimulated apoptotic breast cancer cell death with 31.6-fold (16.13% compared to 0.51 for the control) at pre-G1 and G2/M-phase cell cycle arrest and blocked the progression of MCF-7 cells. Moreover, the identified compounds especially <b>1</b> were found to have high binding affinity towards both TPK and VEGFR-2 through the molecular docking studies which highlight its mode of action. HighlightsChemical profiling of <i>Phyllostachys heterocycla</i> bark nonpolar extract was fully identified.Glyceryl 1-monopalmitate showed highly promising effect against the MCF-7 cells with (IC<sub>50</sub> = 19.78 µM) compared to 5-FU (26.98 µM).Glyceryl 1-monopalmitate significantly stimulated apoptotic breast cancer cell death with 31.6-fold by arresting cell cycle at G2/M and preG1 phases.Molecular docking simulation showed good binding affinities towards TPK and VEGFR-2 proteins. Chemical profiling of <i>Phyllostachys heterocycla</i> bark nonpolar extract was fully identified. Glyceryl 1-monopalmitate showed highly promising effect against the MCF-7 cells with (IC<sub>50</sub> = 19.78 µM) compared to 5-FU (26.98 µM). Glyceryl 1-monopalmitate significantly stimulated apoptotic breast cancer cell death with 31.6-fold by arresting cell cycle at G2/M and preG1 phases. Molecular docking simulation showed good binding affinities towards TPK and VEGFR-2 proteins. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.14945422
title: Prophylactic and therapeutic potential of selected immunomodulatory agents from Ayurveda against coronaviruses amidst the current formidable scenario: an <i>in silico</i> analysis

description: There is currently a dearth of specific therapies to treat respiratory infections caused by the three related species of coronaviruses <i>viz</i>. SARS-CoV-2, SARS-CoV and MERS-CoV. Prevention from disease is currently the safest and most convenient alternative available. The present study aimed to evaluate the preventive and therapeutic effect of fifteen phytoconstituents from medicinal plants of Ayurveda against coronaviruses by <i>in silico</i> screening. All the phytoconstituents exhibited rapid GI absorption and bioavailability and most of them had no toxicity <i>versus</i> reference drug chloroquine. BAS analyses revealed that most of the phytocomponents had favorable bioactivity scores towards biological target proteins. Principal component analysis revealed that most of the phytoconstituents fell close to chloroquine in 3D projection of chemical space. Affinity of phytoconstituents towards SARS-CoV-2 spike protein-human ACE2 complex decreased as isomeldenin &gt; tinosporaside &gt; EGCG whereas in case of unbound ACE2, the strength of binding followed the order isomeldenin &gt; tinosporaside &gt; ellagic acid. Towards SARS-CoV-2 main and papain-like proteases, the affinity decreased as isomeldenin &gt; EGCG &gt; tinosporaside and EGCG &gt; tinosporaside &gt; isomeldenin, respectively. Most phytoconstituents displayed significant binding kinetics to the selected protein targets than chloroquine. SAR analysis revealed that isomeldenin, tinosporaside, EGCG and ellagic acid bind to viral spike glycoproteins <i>via</i> H-bond, Pi-Pi, Pi-sigma and Pi-alkyl type interactions. Molecular dynamics simulation of isomeldenin and EGCG with SARS-CoV and SARS-CoV-2 spike glycoproteins exhibited low deviations throughout the 100 ns simulation indicating good stability and compactness of the protein-ligand complexes. Thus, the above four phytoconstituents have the potential to emerge as prophylactic and therapeutic agents against coronaviruses if investigated further <i>in vitro</i> and <i>in vivo</i>. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.14945422.v1
title: Prophylactic and therapeutic potential of selected immunomodulatory agents from Ayurveda against coronaviruses amidst the current formidable scenario: an <i>in silico</i> analysis

description: There is currently a dearth of specific therapies to treat respiratory infections caused by the three related species of coronaviruses <i>viz</i>. SARS-CoV-2, SARS-CoV and MERS-CoV. Prevention from disease is currently the safest and most convenient alternative available. The present study aimed to evaluate the preventive and therapeutic effect of fifteen phytoconstituents from medicinal plants of Ayurveda against coronaviruses by <i>in silico</i> screening. All the phytoconstituents exhibited rapid GI absorption and bioavailability and most of them had no toxicity <i>versus</i> reference drug chloroquine. BAS analyses revealed that most of the phytocomponents had favorable bioactivity scores towards biological target proteins. Principal component analysis revealed that most of the phytoconstituents fell close to chloroquine in 3D projection of chemical space. Affinity of phytoconstituents towards SARS-CoV-2 spike protein-human ACE2 complex decreased as isomeldenin &gt; tinosporaside &gt; EGCG whereas in case of unbound ACE2, the strength of binding followed the order isomeldenin &gt; tinosporaside &gt; ellagic acid. Towards SARS-CoV-2 main and papain-like proteases, the affinity decreased as isomeldenin &gt; EGCG &gt; tinosporaside and EGCG &gt; tinosporaside &gt; isomeldenin, respectively. Most phytoconstituents displayed significant binding kinetics to the selected protein targets than chloroquine. SAR analysis revealed that isomeldenin, tinosporaside, EGCG and ellagic acid bind to viral spike glycoproteins <i>via</i> H-bond, Pi-Pi, Pi-sigma and Pi-alkyl type interactions. Molecular dynamics simulation of isomeldenin and EGCG with SARS-CoV and SARS-CoV-2 spike glycoproteins exhibited low deviations throughout the 100 ns simulation indicating good stability and compactness of the protein-ligand complexes. Thus, the above four phytoconstituents have the potential to emerge as prophylactic and therapeutic agents against coronaviruses if investigated further <i>in vitro</i> and <i>in vivo</i>. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.14778533
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
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.14778533.v2
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