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Identification of inhibitors against ?-Isopropylmalate Synthase of Mycobacterium tuberculosis using docking-MM/PBSA hybrid approach.

ABSTRACT: ?-Isopropylmalate Synthase (?-IPMS) encoded by leuA in Mycobacterium tuberculosis (M.tb) is involved in the leucine biosynthesis pathway and is extremely critical for the synthesis of branched-chain amino acids (leucine, isoleucine and valine). ?-IPMS activity is required not only for the proliferation of M.tb but is also indispensable for its survival during the latent phase of infection. It is absent in humans and is widely regarded as one of the validated drug targets against Tuberculosis (TB). Despite its essentiality, any study on designing of potential chemical inhibitors against ?-IPMS has not been reported so far. In the present study, in silico identification of putative inhibitors against ?-IPMS exploring three chemical databases i.e. NCI, DrugBank and ChEMBL is reported through structurebased drug design and filtering of ligands based on the pharmacophore feature of the actives. In the absence of experimental results of any inhibitor against ?-IPMS, a stringent validation of docking results is done by comparing with molecular mechanics/Poisson- Boltzmann surface area (MM/PBSA) calculations by investigating two more proteins for which experimental results are known.

SUBMITTER: Pandey P

PROVIDER: S-EPMC5498780 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Identification of inhibitors against α-Isopropylmalate Synthase of Mycobacterium tuberculosis using docking-MM/PBSA hybrid approach.

Pandey Preeti P Lynn Andrew M AM Bandyopadhyay Pradipta P

Bioinformation 20170531 5

α-Isopropylmalate Synthase (α-IPMS) encoded by leuA in Mycobacterium tuberculosis (M.tb) is involved in the leucine biosynthesis pathway and is extremely critical for the synthesis of branched-chain amino acids (leucine, isoleucine and valine). α-IPMS activity is required not only for the proliferation of M.tb but is also indispensable for its survival during the latent phase of infection. It is absent in humans and is widely regarded as one of the validated drug targets against Tuberculosis (TB ...[more]

PMID: 28690380

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Project description:The coronavirus disease 2019 (COVID-19) is a pandemic that has severely posed substantial health challenges and claimed millions of lives. Though vaccines have been produced to stem the spread of this disease, the death rate remains high since drugs used for treatment have therapeutic challenges. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes the disease, has a slew of potential therapeutic targets. Among them is the furin protease, which has a cleavage site on the virus's spike protein. The cleavage site facilitates the entry of the virus into human cells via cell-cell fusion. This critical involvement of furin in the disease pathogenicity has made it a viable therapeutic strategy against the virus. This study employs the consensus docking approach using HYBRID and AutoDock Vina to virtually screen a pre-filtered library of 3942 natural product compounds of African origin against the human furin protease (PDB: 4RYD). Twenty of these compounds were selected as hits after meeting molecular docking cut-off of - 7 kcal.mol-1, pose alignment inspection, and having favorable furin-ligand interactions. An area under the curve (AUC) value of 0.72 was computed from the receiver operator characteristic (ROC) curve, and Boltzmann-enhanced discrimination of the ROC curve (BEDROC) value of 0.65 showed that AutoDock Vina was a reasonable tool for selecting actives for this target. Seven of these hits were proposed as potential leads having had bonding interactions with catalytic triad residues Ser368, His194, and Asp153, and other essential residues in the active site with plausible binding free energies between - 189 and - 95 kJ/mol from the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations as well as favorable ADME/Tox properties. The molecules were also predicted as antiviral, anti-inflammatory, membrane permeability inhibitors, RNA synthesis inhibitors, cytoprotective, and hepatoprotective with probable activity (Pa) above 0.5 and probable inactivity values below 0.1. Some of them also have anti-influenza activity. Influenza virus has many similarities with SARS-CoV-2 in their mode of entry into human cells as both are facilitated by the furin protease. Pinobanksin 3-(E)-caffeate, one of the potential leads is a propolis compound. Propolis compounds have shown inhibitory effects against ACE2, TMPRSS2, and PAK1 signaling pathways of SARS-CoV-2 in previous studies. Likewise, quercitrin is structurally similar to isoquercetin, which is currently in clinical trials as possible medication for COVID-19.Supplementary informationThe online version contains supplementary material available at 10.1007/s11224-022-02056-1.

Dataset Information

Identification of inhibitors against ?-Isopropylmalate Synthase of Mycobacterium tuberculosis using docking-MM/PBSA hybrid approach.

Publications

Identification of inhibitors against α-Isopropylmalate Synthase of Mycobacterium tuberculosis using docking-MM/PBSA hybrid approach.

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