Target based synthesis of novel heterocyclic chemical entity and their application

Abstract

The Enoyl acyl carrier protein reductase (InhA) from Mycobacterium Tuberculosis, is one of the most important enzymes involved in type II fatty acid biosynthesis pathway to synthesize mycolic acid of Mycobacterium tuberculosis. Therefore, inhibitors of InhA are useful analogues for the treatment of tuberculosis due to this reason InhA selected as the target for the study. In this present study, we have described ADME, docking study combined with pharmacophore study as a rotational strategy to the identification of novel leads or hits. Firstly, we have designed ligand and separated into four different sets of a library for easy understanding. The basic ligands were selected based on medicinal important of the compounds and literature survey. The library of ligand more than 50,000 compounds in each set have been developed using Enumeration module in maestro. These compounds were subjected to ADME pharmacokinetics study for the primary elimination of compounds. The compounds which have good ADME properties have further subjected to virtual screening using Glide at the active site of Enoyl-ACP reductase using four different PDB (PDB ID: 2B37, 1QG6, 4TZK, 4TZT). Furthermore, the pharmacophore hypothesis of highest glide scoring ligands was generated with the help of PHASE module. The resulting form this study highlights that the few compounds could be promising future inhibitors for chemotherapeutic prevention of Tuberculosis. The ADME study suggests that the few compounds have better pharmacokinetics properties than 95% drug molecules. The molecular docking study also showed that the compounds have a good binding affinity with the highest binding score which is better than native ligands of the targeted protein. The pharmacophore development study supports our prediction regarding the minimum features required for the molecules to behave as Enoyl-ACP reductase inhibitors. The generated hits form the present study can be synthesized and will be tested in vivo as future significant anti-tuberculosis agents.