Virtual Screening and Synthesis of Novel Antitubercular Agents Through Interaction-Based Pharmacophore and Molecular Docking Studies
Jae Wan Jang,
Seung Kon Hong,
Eunice Eunkyeong Kim,
Ae Nim Pae,
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.
Keywords: Amidoethylamine, antitubercular agents, computational chemistry, InhA inhibitors, molecular docking,
Mycobacterium tuberculosis, pharmacophore, virtual screening.
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