Virtual screening and synthesis of novel antitubercular agents through interaction-based pharmacophore and molecular docking studies.

Deepak Bhattarai, Muhammad Muddassar, Jae Wan Jang, Seung Kon Hong, Eunice Eunkyeong Kim, Taegwon Oh, Sang-Nae Cho, Ae Nim Pae, Gyochang Keum

Index: Curr. Comput. Aided. Drug Des. 10 , 383-92, (2015)

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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.