title: Virtual screening and synthesis of novel antitubercular agents through interaction-based pharmacophore and molecular docking studies.
abstract: Tuberculosis continues to become a major threat and wide spreading disease though out the world. Therefore it is required to identify the new drugs for the treatment of tuberculosis with better activity profile than the prevalent compounds. In present study we have screened and modified the antitubercular compounds from commercial chemical database using the interaction-based pharmacophore and molecular docking studies. In the first step different pharmacophores of cocrystal structures of enyol acyl carrier reductase (also known as InhA) proteins (2B36 and 3FNG) were generated and employed for screening of ChemDiv database. Four different pharmacophore hypothesis retrieved 3456 hits from approximately 0.67 million compounds. In the second filter, these hit molecules were subjected to the molecular docking studies in 2NSD and 3FNG crystal structures. On the basis of high fit values, GScore, structural diversity and visual inspection, one hundred compounds were selected, purchased and subjected to experimental validation for antitubercular activity against H37Rv Mycobacterium tuberculosis (MTB) strain. Three compounds showed the minimal inhibitory concentration (MIC) value at 16 μg/mL and one compound VH04 showed the value at 1 μg/mL. Then a more active amidoethylamine compound was developed by chemical modifications of the virtual hit VH04 against the MTB strain. We believe that this newly identified scaffold could be useful for the optimization of lead from hit compounds of new antitubercular agents.
authors: Deepak
authors: D
authors: Bhattarai
authors: Muhammad
authors: M
authors: Muddassar
authors: Jae Wan
authors: JW
authors: Jang
authors: Seung Kon
authors: SK
authors: Hong
authors: Eunice Eunkyeong
authors: EE
authors: Kim
authors: Taegwon
authors: T
authors: Oh
authors: Sang-Nae
authors: SN
authors: Cho
authors: Ae Nim
authors: AN
authors: Pae
authors: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Hwarangro 14-gil 5 Seongbuk-gu, Seoul 136-791, Republic of Korea. gkeum@kist.re.kr.
authors: Gyochang
authors: G
authors: Keum
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D001665:Binding Sites; D062126:Databases, Chemical; D015195:Drug Design; D005021:Ethylamines / Q000138:chemical synthesis* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D005021:Ethylamines; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium