title: 3D-QSAR Selectivity Analysis of 1-Adamantyl-3-Heteroaryl Urea Analogs as Potent Inhibitors of Mycobacterium 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.
authors.forename: Preeti
authors.initials: P
authors.lastname: Wadhwa
authors.forename: Sourav
authors.initials: S
authors.lastname: Bagchi
authors.affiliation: Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee-247667, India. anujfcy@iitr.ernet.in.
authors.forename: Anuj
authors.initials: A
authors.lastname: Sharma
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017076:Computer-Aided Design; D055808:Drug Discovery; D004851:Epoxide Hydrolases / Q000378:metabolism; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy* / Q000201:enzymology; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D026901:Membrane Transport Proteins; C000599913:MmpL3 protein, Mycobacterium tuberculosis; D014508:Urea; D004851:Epoxide Hydrolases; D000218:Adamantane