Dataset Information

High-Throughput Virtual Screening, Molecular Dynamics Simulation, and Enzyme Kinetics Identified ZINC84525623 as a Potential Inhibitor of NDM-1.

ABSTRACT: The bacteria expressing New Delhi Metallo-?-lactamase-1 (NDM-1) can hydrolyze all ?-lactam antibiotics including carbapenems, causing multi-drug resistance. The worldwide emergence and dissemination of gene blaNDM-1 (produces NDM-1) in hospital and community settings, rising problems for public health. Indeed, there is an urgent need for NDM-1 inhibitors to manage antibiotic resistance. Here, we have identified novel non-?-lactam ring-containing inhibitors of NDM-1 by applying a high-throughput virtual screening of lead-like subset of ZINC database. The screened compounds were followed for the molecular docking, the molecular dynamics simulation, and then enzyme kinetics assessment. The adopted screening procedure funnels out five novel inhibitors of NDM-1 including ZINC10936382, ZINC30479078, ZINC41493045, ZINC7424911, and ZINC84525623. The molecular mechanics-generalized born surface area and molecular dynamics (MD) simulation showed that ZINC84525623 formed the most stable complex with NDM-1. Furthermore, analyses of the binding pose after MD simulation revealed that ZINC84525623 formed two hydrogen bonds (electrostatic and hydrophobic interaction) with key amino acid residues of the NDM-1 active site. The docking binding free energy and docking binding constant for the ZINC84525623 and NDM-1 interaction were estimated to be -11.234 kcal/mol, and 1.74 × 10? M-1 respectively. Steady-state enzyme kinetics in the presence of ZINC84525623 show the decreased catalytic efficiency (i.e., kcat/Km) of NDM-1 on various antibiotics. The findings of this study would be helpful in identifying novel inhibitors against other ?-lactamases from a pool of large databases. Furthermore, the identified inhibitor (ZINC84525623) could be developed as efficient drug candidates.

SUBMITTER: Rehman MT

PROVIDER: S-EPMC6412273 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

High-Throughput Virtual Screening, Molecular Dynamics Simulation, and Enzyme Kinetics Identified ZINC84525623 as a Potential Inhibitor of NDM-1.

Rehman Md Tabish MT AlAjmi Mohamed F MF Hussain Afzal A Rather Gulam Mohmad GM Khan Meraj A MA

International journal of molecular sciences 20190214 4

The bacteria expressing New Delhi Metallo-β-lactamase-1 (NDM-1) can hydrolyze all β-lactam antibiotics including carbapenems, causing multi-drug resistance. The worldwide emergence and dissemination of gene <i>bla</i><sub>NDM-1</sub> (produces NDM-1) in hospital and community settings, rising problems for public health. Indeed, there is an urgent need for NDM-1 inhibitors to manage antibiotic resistance. Here, we have identified novel non-β-lactam ring-containing inhibitors of NDM-1 by applying ...[more]

PMID: 30769822

Similar Datasets

Project description:Multidrug resistant bacteria are a major therapeutic challenge. CTX-M-type enzymes are an important group of class A extended-spectrum β-lactamases (ESBLs). ESBLs are the enzymes that arm bacterial pathogens with drug resistance to an array of antibiotics, notably the advanced-generation cephalosporins. The current need for an effective CTX-M-inhibitor is high. The aim of the current study was to identify a promising anti-CTX-M-15 ligand whose chemical skeleton could be used as a 'seed-molecule' for future drug design against resistant bacteria. Virtual screening of 5,000,000 test molecules was performed by 'MCULE Drug Discovery Platform'. 'ADME analyses' was performed by 'SWISS ADME'. TOXICITY CHECKER of MCULE was employed to predict the safety profile of the test molecules. The complex of the 'Top inhibitor' with the 'bacterial CTX-M-15 enzyme' was subjected to 102.25 ns molecular dynamics simulation. This simulation was run for 3 days on a HP ZR30w workstation. Trajectory analyses were performed by employing the macro 'md_analyze.mcr' of YASARA STRUCTURE version 20.12.24.W.64 using AMBER14 force field. YANACONDA macro language was used for complex tasks. Figures, including RMSD and RMSF plots, were generated. Snapshots were acquired after every 250 ps. Finally, two short videos of '41 s' and '1 min and 22 s' duration were recorded. 5-Amino-1-(2H-[1,2,4]triazino[5,6-b]indol-3-yl)-1H-pyrazole-4-carbonitrile, denoted by the MCULE-1352214421-0-56, displayed the most efficient binding with bacterial CTX-M-15 enzyme. This screened molecule significantly interacted with CTX-M-15 via 13 amino acid residues. Notably, nine amino acid residues were found common to avibactam binding (the reference ligand). Trajectory analysis yielded 410 snapshots. The RMSD plot revealed that around 26 ns, equilibrium was achieved and, thereafter, the complex remained reasonably stable. After a duration of 26 ns and onwards until 102.25 ns, the backbone RMSD fluctuations were found to be confined within a range of 0.8-1.4 Å. 5-Amino-1-(2H-[1,2,4]triazino[5,6-b]indol-3-yl)-1H-pyrazole-4-carbonitrile could emerge as a promising seed molecule for CTX-M-15-inhibitor design. It satisfied ADMET features and displayed encouraging 'simulation results'. Advanced plots obtained by trajectory analyses predicted the stability of the proposed protein-ligand complex. 'Hands on' wet laboratory validation is warranted.

Project description:BackgroundThe COVID-19 pandemic, caused by the SARS-CoV-2 virus, has ravaged lives across the globe since December 2019, and new cases are still on the rise. Peoples' ongoing sufferings trigger scientists to develop safe and effective remedies to treat this deadly viral disease. While repurposing the existing FDA-approved drugs remains in the front line, exploring drug candidates from synthetic and natural compounds is also a viable alternative. This study employed a comprehensive computational approach to screen inhibitors for SARS-CoV-2 3CL-PRO (also known as the main protease), a prime molecular target to treat coronavirus diseases.MethodsWe performed 100 ns GROMACS molecular dynamics simulations of three high-resolution X-ray crystallographic structures of 3CL-PRO. We extracted frames at 10 ns intervals to mimic conformational diversities of the target protein in biological environments. We then used AutoDock Vina molecular docking to virtual screen the Sigma-Aldrich MyriaScreen Diversity Library II, a rich collection of 10,000 druglike small molecules with diverse chemotypes. Subsequently, we adopted in silico computation of physicochemical properties, pharmacokinetic parameters, and toxicity profiles. Finally, we analyzed hydrogen bonding and other protein-ligand interactions for the short-listed compounds.ResultsOver the 100 ns molecular dynamics simulations of 3CL-PRO's crystal structures, 6LZE, 6M0K, and 6YB7, showed overall integrity with mean Cα root-mean-square deviation (RMSD) of 1.96 (±0.35) Å, 1.98 (±0.21) Å, and 1.94 (±0.25) Å, respectively. Average root-mean-square fluctuation (RMSF) values were 1.21 ± 0.79 (6LZE), 1.12 ± 0.72 (6M0K), and 1.11 ± 0.60 (6YB7). After two phases of AutoDock Vina virtual screening of the MyriaScreen Diversity Library II, we prepared a list of the top 20 ligands. We selected four promising leads considering predicted oral bioavailability, druglikeness, and toxicity profiles. These compounds also demonstrated favorable protein-ligand interactions. We then employed 50-ns molecular dynamics simulations for the four selected molecules and the reference ligand 11a in the crystallographic structure 6LZE. Analysis of RMSF, RMSD, and hydrogen bonding along the simulation trajectories indicated that S51765 would form a more stable protein-ligand complexe with 3CL-PRO compared to other molecules. Insights into short-range Coulombic and Lennard-Jones potentials also revealed favorable binding of S51765 with 3CL-PRO.ConclusionWe identified a potential lead for antiviral drug discovery against the SARS-CoV-2 main protease. Our results will aid global efforts to find safe and effective remedies for COVID-19.

Project description:AbstractOne in every two humans is having Helicobacter pylori (H. pylori) in stomach causing gastric ulcer. Emergence of several drugs in eliminating H. pylori has paved way for emergence of multidrug resistance in them. This resistance is thriving and thereby necessitating the need of a potent drug. Identifying a potential target for medication is crucial. Bacterial 5'-methylthioadenosine/S-enosyl homocysteine nucleosidase (MTAN) is a multifunctional enzyme that controls seven essential metabolic pathways. It functions as a catalyst in the hydrolysis of the N-ribosidic bond of adenosine-based metabolites: S-adenosylhomocysteine (SAH), 5'-methylthioadenosine (MTA), 5'-deoxyadenosine (5'-DOA), and 6-amino-6-deoxyfutalosine. H. pylori unlike other bacteria and humans utilises an alternative pathway for menaquinone synthesis. It utilises Futosiline pathway for menaquinone synthesis which are obligatory component in electron transport pathway. Therefore, the enzymes functioning in this pathway represent them-self as a point of attack for new medications. We targeted MTAN protein of H. pylori to find out a potent natural hit to inhibit its growth. A comparative analysis was made with potent H. pylori MTAN (HpMTAN) known inhibitor, 5'-butylthio-DADMe-Immucillin-A (BuT-DADMe-ImmA) and ZINC natural subset database. Optimized ligands from the ZINC natural database were virtually screened using ligand based pharmacophore hypothesis to obtain the most efficient and potent inhibitors for HpMTAN. The screened leads were evaluated for their therapeutic likeness. Furthermore, the ligands that passed the test were subjected for MM-GBSA with MTAN to reveal the essential features that contributes selectivity. The results showed that Van der Waals contributions play a central role in determining the selectivity of MTAN. Molecular dynamics (MD) studies were carried out for 100 ns to assess the stability of ligands in the active site. MD analysis showed that binding of ZINC00490333 with MTAN is stable compared to reference inhibitor molecule BuT-DADMe-ImmA. Among the natural inhibitors screened after various docking procedures ZINC00490333 has highest binding score for HpMTAN (- 13.987). The ZINC inhibitor was successful in reproducing the BuT-DADMe-ImmA interactions with HpMTAN. Hence we suggest that ZINC00490333 compound may represent as a good lead in designing novel potent inhibitors of HpMTAN. This in silico approach indicates the potential of this molecule for advancing a further step in gastric ulcer treatment.Graphic abstractSupplementary informationThe online version contains supplementary material available at 10.1007/s40203-021-00081-2.

Dataset Information

High-Throughput Virtual Screening, Molecular Dynamics Simulation, and Enzyme Kinetics Identified ZINC84525623 as a Potential Inhibitor of NDM-1.

Publications

High-Throughput Virtual Screening, Molecular Dynamics Simulation, and Enzyme Kinetics Identified ZINC84525623 as a Potential Inhibitor of NDM-1.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets