Abstract: IspE contributes to the fourth step of non-mevalonate pathway in Mycobacterium tuberculosis and other pathogenic species. The non-mevalonate pathway is engaged in the synthesis of isoprenoid precursor. The precursors of the isoprenoids are the isopentenyl diphosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). IspE catalyzes the transfer of γ-phosphoryl group from ATP to 4-diphosphocytidyl-2C-methyl-d-erythritol (CDP-ME) resulting in 4-diphosphocytidyl-2C-methyl-D-erythritol-2-phosphate (CDP-ME2P). Based on the crystal structure of IspE complex with AMP-PNP from Mycobacterium tuberculosis, the virtual screening was carried out using ZINC database. The pharmacophore model was developed based on the AMP-PNP interactions with IspE. A subset of 5805 molecules was extracted from ZINC database utilizing the developed pharmacophore model. Through the docking and binding affinity approach, five novel compounds were identified that may act as inhibitors of IspE. Further, the molecular dynamics simulation (MD simulation) revealed that four compounds (compound 1, 2, 3 and 4) among them are more stable in the active site. The MMPBSA analysis also supports the four compounds as good inhibitors in term of binding energy. More interestingly, these compounds show diversity in their structure and also show no resemblance with other published inhibitors. As these compounds belong to the different class of compound, this study is providing an opportunity to further synthesize the derivatives of each compound for the optimization of their inhibitory activity. Therefore, in the present study, five compounds were described as a novel lead compounds that will act as good starting point for the drug discovery.
Keywords: IspE Inhibitors, Molecular docking, MD Simulation, ZINC database, MMPBSA analysis, Mycobacterium tuberculosis.
Title: In Silico Identification of Lead Compounds for the Inhibition of Mycobacterium Tuberculosis IspE Using Complex Based Pharmacophore Mapping, Virtual Screening and Molecular Dynamics Simulation
Author: Eman Abdullah Almuqri, Mohammad Teimouri, Junaid Muhammad
International Journal of Life Sciences Research
ISSN 2348-3148 (online), ISSN 2348-313X (Print)
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