Abstract
A 3D-QSAR selectivity analysis of 53 adamantyl heteroaryl urea derivatives active against M. tuberculosis is reported. These analogs inhibit Mycobacterial Membrane Protein Large 3 (MmpL3), a proposed transporter for cell wall mycolic acids. However, these analogs also exhibit affinity towards human soluble epoxide hydrolase (sEH) enzyme, making them pharmacologically undesirable. Thus, COMFA and CoMSIA selective studies viz ligand and receptor-based alignment has been described to evaluate key pharmacophoric structural features that may possibly play a crucial role for selective inhibition. This hypothesis was experimentally validated and successfully tested on four novel adamantyl urea based derivatives with known biological activity. Therefore, this approach may pave way to novel specific inhibitors in tuberculosis drug discovery process.
Keywords: CoMFA, CoMSIA, docking, homology modelling, human sEH, MmpL3, tuberculosis.
Current Computer-Aided Drug Design
Title:3D-QSAR Selectivity Analysis of 1-Adamantyl-3-Heteroaryl Urea Analogs as Potent Inhibitors of Mycobacterium tuberculosis
Volume: 11 Issue: 2
Author(s): Preeti Wadhwa, Sourav Bagchi and Anuj Sharma
Affiliation:
Keywords: CoMFA, CoMSIA, docking, homology modelling, human sEH, MmpL3, tuberculosis.
Abstract: A 3D-QSAR selectivity analysis of 53 adamantyl heteroaryl urea derivatives active against M. tuberculosis is reported. These analogs inhibit Mycobacterial Membrane Protein Large 3 (MmpL3), a proposed transporter for cell wall mycolic acids. However, these analogs also exhibit affinity towards human soluble epoxide hydrolase (sEH) enzyme, making them pharmacologically undesirable. Thus, COMFA and CoMSIA selective studies viz ligand and receptor-based alignment has been described to evaluate key pharmacophoric structural features that may possibly play a crucial role for selective inhibition. This hypothesis was experimentally validated and successfully tested on four novel adamantyl urea based derivatives with known biological activity. Therefore, this approach may pave way to novel specific inhibitors in tuberculosis drug discovery process.
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Wadhwa Preeti, Bagchi Sourav and Sharma Anuj, 3D-QSAR Selectivity Analysis of 1-Adamantyl-3-Heteroaryl Urea Analogs as Potent Inhibitors of Mycobacterium tuberculosis, Current Computer-Aided Drug Design 2015; 11 (2) . https://dx.doi.org/10.2174/1573409911666150803154114
DOI https://dx.doi.org/10.2174/1573409911666150803154114 |
Print ISSN 1573-4099 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6697 |
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