Design QSAR Studies of New Anti TB Drugs and Evaluation of their Microbiological and Pharmacological Activities

Abstract

The better understanding of protein ligand interactions and molecular recognition, their appropriate use in a drug discovery process have improved the ability to critically assess the identification and optimization of lead compounds which have high potential for generating new therapeutic agents. We have identified and proposed some novel, potential lead molecules as Dihydrofolate Reductase (DHFR) inhibitors against Mycobacterium tuberculosis using analog and structure based studies which are found to be potential leads for further research in future. The pharmacophore model has been well validated to be of high predictability for estimating the activities over a variety of compounds and evaluating the mapping of diverse active compounds onto the pharmacophore. Pharmacophore studies indicated that the best DHFR inhibitor model hypo 1 consists of 1) two hydrogen bond acceptors (HBA), 2) one hydrophobic aliphatic (H) and 3) one hydrophobic aromatic (R) features. The chemical feature-based pharmacophore models of DHFR inhibitors have been developed with the aid of Hip Hop and Hypo Refine modules in Catalyst® program package. CONCLUSION: Focusing on an area such as the folate pathway, with its rich history of successful drugs, is therefore a promising way forward. A combination of Virtual screening (Pharmacophore modeling, docking) and 3D-QSAR studies has led to predictive and meaningful models of potent MtbDHFR inhibitors, which provide valuable directions to our ongoing endeavor of rationally designing more potent antitubercular agents. The observed infection profile and therapeutic outcomes in this CFU count method using mice model suggest that it can be used as additional, pharmacologically relevant information to develop novel antitubercular compounds at the interface of discovery and development. In conclusion, the present study provides important structural insights of benzothiazole and benzimidazole chemical moieties in designing better MtbDHFR inhibitors as potent antitubercular agents.