cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.28547539
title: Phytochemical-based drug designing against efflux-pump of ESKAPE pathogen to combat multidrug-resistant: an <i>in silico</i> study

description: The <i>Enterococcus faecium</i>, <i>Staphylococcus aureus</i>, <i>Klebsiella pneumoniae</i>, <i>Acinetobacter baumannii</i>, <i>Pseudomonas aeruginosa</i> and <i>Enterobacter species</i> are ciphered as ESKAPE pathogens leading agents for multidrug resistance (MDR) related infections. The current research study used kanamycin nucleotidyltransferase (PDB ID: 1KNY), OXA-24 class D beta-lactamase (PDB ID: 3ZNT), efflux pump proteins as a target to identify potential inhibitor phytochemical for ameliorating antimicrobial resistance caused by ESKAPE pathogens. A total of 61 MDR genes of ESKAPE pathogens were scrutinized phylogenetically and protein–protein interaction (PPIs) analysis were performed. The target proteins for structure-based drug design were culled based on functional partners of efflux pump proteins obtained after PPIs analysis in all ESKAPE pathogens. We deployed a comprehensive sequential filtering approach including high throughput virtual screening of an in-house created bioactive phytochemicals library from the IMPPAT database. First, a molecular docking-based high throughput virtual screening process, followed by meticulous filtering of hits based on binding energy and detailed active-site interaction analysis was performed on each target protein separately. During this stage, native ligands of the target proteins were deployed as a control ligand and for docking protocol validation. These 50 top phytochemicals against both proteins were culled. Then filtration of hits was done based on pharmacokinetics, toxicity and bioactivity of phytochemicals. The retained phytochemicals against each protein were analyzed through density functional theory (DFT) to check potential reactivity. After, analyzing DFT-based energy calculations final lead phytochemicals were selected. The lead phytochemical stability within respective active-site and dynamic behavior was analyzed through molecular dynamic (MD) simulations and principal component analysis (PCA). In this way, diosgenin and paulownin phytochemicals were identified as a lead inhibitor ligand against 1KNY and 3ZNT target receptors, respectively. The 1KNY–diosgenin and 3ZNT–paulownin complexes exhibited binding energies of −8.1 kcal/mol and −9.0 kcal/mol, respectively, forming hydrogen bonds with specific key residues (1KNY-Arg22, Ser105, Thr186) and (3ZNT-Trp221, Tyr 112, Met114) displaying stable dynamic behavior during 100 ns MD simulation, with DFT-based energy gaps of −0.254 52 eV and −0.195 87 eV, respectively, suggesting greater stability compared to control ligands. The diosgenin and paulownin phytochemicals are promising starting natural candidates for drug development against multidrug-resistant infections cure.
DOI: 10.6084/m9.figshare.28547539.v1
title: Phytochemical-based drug designing against efflux-pump of ESKAPE pathogen to combat multidrug-resistant: an <i>in silico</i> study

description: The <i>Enterococcus faecium</i>, <i>Staphylococcus aureus</i>, <i>Klebsiella pneumoniae</i>, <i>Acinetobacter baumannii</i>, <i>Pseudomonas aeruginosa</i> and <i>Enterobacter species</i> are ciphered as ESKAPE pathogens leading agents for multidrug resistance (MDR) related infections. The current research study used kanamycin nucleotidyltransferase (PDB ID: 1KNY), OXA-24 class D beta-lactamase (PDB ID: 3ZNT), efflux pump proteins as a target to identify potential inhibitor phytochemical for ameliorating antimicrobial resistance caused by ESKAPE pathogens. A total of 61 MDR genes of ESKAPE pathogens were scrutinized phylogenetically and protein–protein interaction (PPIs) analysis were performed. The target proteins for structure-based drug design were culled based on functional partners of efflux pump proteins obtained after PPIs analysis in all ESKAPE pathogens. We deployed a comprehensive sequential filtering approach including high throughput virtual screening of an in-house created bioactive phytochemicals library from the IMPPAT database. First, a molecular docking-based high throughput virtual screening process, followed by meticulous filtering of hits based on binding energy and detailed active-site interaction analysis was performed on each target protein separately. During this stage, native ligands of the target proteins were deployed as a control ligand and for docking protocol validation. These 50 top phytochemicals against both proteins were culled. Then filtration of hits was done based on pharmacokinetics, toxicity and bioactivity of phytochemicals. The retained phytochemicals against each protein were analyzed through density functional theory (DFT) to check potential reactivity. After, analyzing DFT-based energy calculations final lead phytochemicals were selected. The lead phytochemical stability within respective active-site and dynamic behavior was analyzed through molecular dynamic (MD) simulations and principal component analysis (PCA). In this way, diosgenin and paulownin phytochemicals were identified as a lead inhibitor ligand against 1KNY and 3ZNT target receptors, respectively. The 1KNY–diosgenin and 3ZNT–paulownin complexes exhibited binding energies of −8.1 kcal/mol and −9.0 kcal/mol, respectively, forming hydrogen bonds with specific key residues (1KNY-Arg22, Ser105, Thr186) and (3ZNT-Trp221, Tyr 112, Met114) displaying stable dynamic behavior during 100 ns MD simulation, with DFT-based energy gaps of −0.254 52 eV and −0.195 87 eV, respectively, suggesting greater stability compared to control ligands. The diosgenin and paulownin phytochemicals are promising starting natural candidates for drug development against multidrug-resistant infections cure.
DOI: 10.6084/m9.figshare.25737822
title: Effect of irradiated nonionic surfactant on drug-protein binding

description: In this work, the effect of γ-irradiated surfactants on drug–protein binding has been assessed. Irradiated aqueous solutions of Pluronic F-127, Pluronic L-35, Tween 20, and Tween 80 surfactants were used. Gamma irradiation was carried out for three different doses, to these four surfactants viz., 6, 30, and 36 kGy. Two drugs, Ornidazole (ONZ) and Telmisartan (TMS) were used for the binding study. The effect of four irradiated surfactants in the presence of drug – Bovine serum albumin (BSA) protein was analyzed. The drug solutions in methanol-aqueous media were combined with BSA in the initial step. In the next two succeeding steps, drug–BSA interaction in the presence of unirradiated and irradiated surfactants were carried out. The results of drug-BSA due to addition of irradiated and unirradiated surfactants were compared. The interaction processes were assessed through UV Spectroscopy, DLS, zeta potential, turbidity, and docking studies. Improved binding was observed for both the drugs and four surfactants for irradiated surfactants as determined from the binding constant values using UV spectroscopic studies. The DLS measurements demonstrated no general trend of increase or decrease in micellar size with absorbed dose. The binding and change in the size of micelles were observed to be highly drug and surfactant-specific. Among the four surfactants, irradiated Pluronic F-127 showed higher binding affinity. To the best of our knowledge, this is the first report on the effect of γ-irradiated surfactant on drug–BSA interaction. This can be applied to other drug–protein systems to tune their interaction to the required level.
DOI: 10.6084/m9.figshare.25737822.v1
title: Effect of irradiated nonionic surfactant on drug-protein binding

description: In this work, the effect of γ-irradiated surfactants on drug–protein binding has been assessed. Irradiated aqueous solutions of Pluronic F-127, Pluronic L-35, Tween 20, and Tween 80 surfactants were used. Gamma irradiation was carried out for three different doses, to these four surfactants viz., 6, 30, and 36 kGy. Two drugs, Ornidazole (ONZ) and Telmisartan (TMS) were used for the binding study. The effect of four irradiated surfactants in the presence of drug – Bovine serum albumin (BSA) protein was analyzed. The drug solutions in methanol-aqueous media were combined with BSA in the initial step. In the next two succeeding steps, drug–BSA interaction in the presence of unirradiated and irradiated surfactants were carried out. The results of drug-BSA due to addition of irradiated and unirradiated surfactants were compared. The interaction processes were assessed through UV Spectroscopy, DLS, zeta potential, turbidity, and docking studies. Improved binding was observed for both the drugs and four surfactants for irradiated surfactants as determined from the binding constant values using UV spectroscopic studies. The DLS measurements demonstrated no general trend of increase or decrease in micellar size with absorbed dose. The binding and change in the size of micelles were observed to be highly drug and surfactant-specific. Among the four surfactants, irradiated Pluronic F-127 showed higher binding affinity. To the best of our knowledge, this is the first report on the effect of γ-irradiated surfactant on drug–BSA interaction. This can be applied to other drug–protein systems to tune their interaction to the required level.
DOI: 10.6084/m9.figshare.28504273
title: Electric field-induced conformational dynamics of CA9: a potential biomarker for glioblastoma multiforme

description: GBM, a malignant brain tumor prevalent in adults, can be treated using Electric field (EF) therapy. However, the underlying mechanism of EF-based GBM therapy is not well understood. In this study, we used bioinformatics and MD analysis to explore CA9 in EF therapy for GBM. <i>CA9</i> was identified as a differentially expressed gene (DEG) sensitive to EF stimulation in GBM using GEO and TCGA for integrated analysis. Elevated <i>CA9</i> expression was associated with reduced overall survival in GBM patients, indicating that CA9 was an adverse prognostic factor. Single-cell data demonstrated that <i>CA9</i> expression was significantly higher in GBM cells than in normal cells, suggesting that CA9 could be an EF-sensitive biomarker for GBM. GSVA analysis suggested that <i>CA9</i> was related to hypoxia and glucose metabolism in glioblastoma. MD simulations were employed to examine the impact of EF (0 V/nm ≤ <i>E</i> ≤ 0.5 V/nm) on the conformation of the CA9 protein, including RMSF, RMSD, Rg, secondary structure, and dipole moment. The CA9 protein structure was altered with different EF intensities, affecting the motion of protein atoms in an EF intensity-dependent manner. The number of hydrogen bonds was significantly reduced as the EF intensity increased, indicating that EF disrupted the hydrogen bonds. Additionally, the EF intensity affected the dipole moment and characteristic time. Besides, the <i>CA9</i> gene family analysis suggested that this gene family was highly conserved. Overall, CA9 showed potential as a GBM biomarker sensitive to EF, presenting a prospective target for therapeutic interventions in EF-mediated GBM treatment.
DOI: 10.6084/m9.figshare.28504273.v1
title: Electric field-induced conformational dynamics of CA9: a potential biomarker for glioblastoma multiforme

description: GBM, a malignant brain tumor prevalent in adults, can be treated using Electric field (EF) therapy. However, the underlying mechanism of EF-based GBM therapy is not well understood. In this study, we used bioinformatics and MD analysis to explore CA9 in EF therapy for GBM. <i>CA9</i> was identified as a differentially expressed gene (DEG) sensitive to EF stimulation in GBM using GEO and TCGA for integrated analysis. Elevated <i>CA9</i> expression was associated with reduced overall survival in GBM patients, indicating that CA9 was an adverse prognostic factor. Single-cell data demonstrated that <i>CA9</i> expression was significantly higher in GBM cells than in normal cells, suggesting that CA9 could be an EF-sensitive biomarker for GBM. GSVA analysis suggested that <i>CA9</i> was related to hypoxia and glucose metabolism in glioblastoma. MD simulations were employed to examine the impact of EF (0 V/nm ≤ <i>E</i> ≤ 0.5 V/nm) on the conformation of the CA9 protein, including RMSF, RMSD, Rg, secondary structure, and dipole moment. The CA9 protein structure was altered with different EF intensities, affecting the motion of protein atoms in an EF intensity-dependent manner. The number of hydrogen bonds was significantly reduced as the EF intensity increased, indicating that EF disrupted the hydrogen bonds. Additionally, the EF intensity affected the dipole moment and characteristic time. Besides, the <i>CA9</i> gene family analysis suggested that this gene family was highly conserved. Overall, CA9 showed potential as a GBM biomarker sensitive to EF, presenting a prospective target for therapeutic interventions in EF-mediated GBM treatment.
DOI: 10.6084/m9.figshare.28559184
title: Computational design of a fimbriae-derived multi-epitope vaccine candidate against <i>Klebsiella pneumoniae</i>

description: <i>Klebsiella pneumoniae</i> is a pathogen that causes infections in various parts of the body, with high mortality rates reported in antibiotic-resistant cases. Treating at-risk individuals requires crucial vaccination efforts due to the challenges that exist. This research involved designing a multi-epitope vaccine from <i>K. pneumoniae</i>’s fimbriae antigens. Optimal T-cell and B-cell epitopes were chosen through <i>in silico</i> studies including epitope-HLAs molecular docking. The multi-epitope was created, featuring antigenic T- and B-cell epitopes, β-defensin as an adjuvant, the PADRE sequence to boost immunogenicity and well-suited linkers. The tertiary structure of the multi-epitope was achieved through modeling and molecular dynamics-based refinements. The construct underwent scrutiny for structural traits, physicochemical properties, conformational B epitope prediction, immune responses simulation, <i>in silico</i> cloning, molecular docking for assay binding to toll-like receptors (TLRs), and deformability studies. The outcomes indicated the vaccine candidate’s positive attributes, encompassing immunogenicity, structure, physicochemical properties, solubility, TLR binding, toxicity, stability, allergenicity, and cross-reactivity. The multi-epitope vaccine candidate exhibits the potential for provoking diverse immune responses against <i>K. pneumoniae</i>. Nevertheless, additional <i>in vitro</i> and <i>in vivo</i> experimental tests are necessary to substantiate its efficacy.
DOI: 10.6084/m9.figshare.28559184.v1
title: Computational design of a fimbriae-derived multi-epitope vaccine candidate against <i>Klebsiella pneumoniae</i>

description: <i>Klebsiella pneumoniae</i> is a pathogen that causes infections in various parts of the body, with high mortality rates reported in antibiotic-resistant cases. Treating at-risk individuals requires crucial vaccination efforts due to the challenges that exist. This research involved designing a multi-epitope vaccine from <i>K. pneumoniae</i>’s fimbriae antigens. Optimal T-cell and B-cell epitopes were chosen through <i>in silico</i> studies including epitope-HLAs molecular docking. The multi-epitope was created, featuring antigenic T- and B-cell epitopes, β-defensin as an adjuvant, the PADRE sequence to boost immunogenicity and well-suited linkers. The tertiary structure of the multi-epitope was achieved through modeling and molecular dynamics-based refinements. The construct underwent scrutiny for structural traits, physicochemical properties, conformational B epitope prediction, immune responses simulation, <i>in silico</i> cloning, molecular docking for assay binding to toll-like receptors (TLRs), and deformability studies. The outcomes indicated the vaccine candidate’s positive attributes, encompassing immunogenicity, structure, physicochemical properties, solubility, TLR binding, toxicity, stability, allergenicity, and cross-reactivity. The multi-epitope vaccine candidate exhibits the potential for provoking diverse immune responses against <i>K. pneumoniae</i>. Nevertheless, additional <i>in vitro</i> and <i>in vivo</i> experimental tests are necessary to substantiate its efficacy.
DOI: 10.6084/m9.figshare.28227333
title: Exploring the conformational space of ROS1 kinase domain and the impact of allosteric mutations

description: Chromosomal rearrangements are common oncogenic events in Non-Small Cell Lung Cancer. An example is the fusion of the ROS1 kinase domain with extracellular receptors. Although the fusion leads to a target that is druggable with multi-kinase inhibitors, several reports indicate the emergence of point mutations leading to drug resistance. Although these mutations are often located in the ATP binding pocket, a subset of them is neighboring the pocket without a direct effect on drug binding. Due to the clinical impact of these allosteric mutations, there is an urge to identify the mechanism of resistance and characterize the pocket for further drug design studies. This study aimed to unravel the resistance mechanism of L1982F and S1986F/Y mutations. The variants were modeled and simulated using classical Molecular Dynamics simulations and accessed for their conformational flexibility. Our results indicate a direct effect of these allosteric mutants in the binding pocket volume with an indication of the G-loop playing a central role.
DOI: 10.6084/m9.figshare.28227333.v1
title: Exploring the conformational space of ROS1 kinase domain and the impact of allosteric mutations

description: Chromosomal rearrangements are common oncogenic events in Non-Small Cell Lung Cancer. An example is the fusion of the ROS1 kinase domain with extracellular receptors. Although the fusion leads to a target that is druggable with multi-kinase inhibitors, several reports indicate the emergence of point mutations leading to drug resistance. Although these mutations are often located in the ATP binding pocket, a subset of them is neighboring the pocket without a direct effect on drug binding. Due to the clinical impact of these allosteric mutations, there is an urge to identify the mechanism of resistance and characterize the pocket for further drug design studies. This study aimed to unravel the resistance mechanism of L1982F and S1986F/Y mutations. The variants were modeled and simulated using classical Molecular Dynamics simulations and accessed for their conformational flexibility. Our results indicate a direct effect of these allosteric mutants in the binding pocket volume with an indication of the G-loop playing a central role.
DOI: 10.6084/m9.figshare.29117805
title: Enhancing thermal stability of pectinase using thermal titration molecular dynamics and density functional theory approach

description: Pectinase, an enzyme primarily produced from <i>Aspergillus niger</i>, is essential in various industrial applications. However, the enzyme’s functionality at high temperatures is challenging, restricting its effectiveness and potential uses. Therefore, the present study investigated the potential of peptide binding to enhance the thermal stability of pectinase. Thermal titration molecular dynamics (MD) simulations were performed at 300, 320, 340 and 360 K to identify regions susceptible to thermal fluctuations. Based on these results, 235,200 peptide sequences were screened to target the detected unstable regions. Machine learning models predicted the peptide activity and 12 promising peptide–protein complexes were identified using docking. Binding free energy calculations showed pep-10 (−19.4 kcal/mol), pep-8 (−17.97 kcal/mol), pep-12 (−15.25 kcal/mol) and pep-6 (−9.86 kcal/mol) as the most promising candidates to improve the thermal stability. Density functional theory calculations showed that pep-12 had the lowest energy of −2365. MD simulations at 360 K for 100 ns demonstrated that pep-12 maintained the most stable conformation with root mean square deviation (0.2–0.25 nm) compared to other peptides. Quantum mechanics/molecular mechanics hybrid approach to examine the mechanism of the pep-12 complex with Pectinase. The outcomes of this study suggested that pep-12 is the most potential candidate for enhancing pectinase thermal stability.
DOI: 10.6084/m9.figshare.29117805.v1
title: Enhancing thermal stability of pectinase using thermal titration molecular dynamics and density functional theory approach

description: Pectinase, an enzyme primarily produced from <i>Aspergillus niger</i>, is essential in various industrial applications. However, the enzyme’s functionality at high temperatures is challenging, restricting its effectiveness and potential uses. Therefore, the present study investigated the potential of peptide binding to enhance the thermal stability of pectinase. Thermal titration molecular dynamics (MD) simulations were performed at 300, 320, 340 and 360 K to identify regions susceptible to thermal fluctuations. Based on these results, 235,200 peptide sequences were screened to target the detected unstable regions. Machine learning models predicted the peptide activity and 12 promising peptide–protein complexes were identified using docking. Binding free energy calculations showed pep-10 (−19.4 kcal/mol), pep-8 (−17.97 kcal/mol), pep-12 (−15.25 kcal/mol) and pep-6 (−9.86 kcal/mol) as the most promising candidates to improve the thermal stability. Density functional theory calculations showed that pep-12 had the lowest energy of −2365. MD simulations at 360 K for 100 ns demonstrated that pep-12 maintained the most stable conformation with root mean square deviation (0.2–0.25 nm) compared to other peptides. Quantum mechanics/molecular mechanics hybrid approach to examine the mechanism of the pep-12 complex with Pectinase. The outcomes of this study suggested that pep-12 is the most potential candidate for enhancing pectinase thermal stability.
DOI: 10.6084/m9.figshare.28532894
title: Network pharmacology exploring the mechanistic role of indirubin phytoconstituent from <i>Indigo naturalis</i> targeting GSK-3<i>β</i> in Alzheimer’s disease

description: One of the most common causes of dementia in older adults is Alzheimer’s disease (AD). Numerous mechanisms, including acetylcholine breakdown, amyloid beta buildup, neurofibrillary tangle accumulation, and inflammation, are involved in the pathogenesis of AD. Different targets have been demonstrated in studies to alleviate the cognitive impairment in AD. In AD, amyloid <i>β</i> impairs phosphatidylinositol-3 (PI3)/Akt signaling, activating GSK-3<i>β</i>. This sequence leads to an increase in the phosphorylation of tau, the creation of neurofibrillary tangles, neuronal death, loss of synapses, and memory impairments, all of which are typical symptoms seen in the brains of individuals with AD. Using network pharmacology, molecular docking, and MD simulations, we have determined that indirubin can selectively interact with glycogen synthase kinase 3 beta (GSK-3<i>β</i>). Traditional Chinese Medicine, including <i>Indigo naturalis, is</i> known to have the ability to control chronic diseases having indirubin as the main phytoconstituent. The binding energy of indirubin was −10.9 kcal/mol, which was better than that of the reference ligand with −9.4 kcal/mol. According to MD simulations, the indirubin-GSK-3<i>β</i> complex remained stable during the simulation, exhibiting an RMSD of 1.90 in comparison to the 2.01 and 2.34 for reference-GSK-3<i>β</i> complex and free protein, respectively. According to our study, indirubin phytoconstituent from <i>Indigo naturalis</i>, targets GSK-3β in AD, additional investigation in the quest for inhibitors of this crucial biological target required further in-vitro/in-vivo experimental validations.