Discovery and evaluation of novel Mycobacterium tuberculosis ketol-acid reductoisomerase inhibitors as therapeutic drug leads

• Published in: Journal of computer-aided molecular design 2019-03, Vol.33 (3), p.357-366
• Main Authors: Krishna, Vagolu Siva, Zheng, Shan, Rekha, Estharla Madhu, Guddat, Luke W., Sriram, Dharmarajan
• Format: Article
• Language: English
• Subjects: Amino acids; Animal Anatomy; Animals; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Biosynthesis; Catalytic Domain; Cell Survival; Chain branching; Chemistry; Chemistry and Materials Science; Computer Applications in Chemistry; Computer Simulation; Databases, Chemical; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes; Etiology; Histology; Inhibitors; Ketol-Acid Reductoisomerase - antagonists & inhibitors; Kinetics; Mice; Molecular docking; Molecular Docking Simulation - methods; Molecular dynamics; Morphology; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - enzymology; Physical Chemistry; Protein Binding; RAW 264.7 Cells; Structure-Activity Relationship; Toxicity; Tuberculosis
• ISSN: 0920-654X; 1573-4951
• DOI: 10.1007/s10822-019-00184-1

Tuberculosis (TB) remains a major threat to human health. This due to the fact that current drug treatments are less than optimal and the increasing occurrence of multi drug-resistant strains of etiological agent, Mycobacterium tuberculosis ( Mt ). Given the wide-spread significance of this disease, we have undertaken a design and evaluation program to discover new anti-TB drug leads. Here, we focused on ketol-acid reductoisomerase (KARI), the second enzyme in the branched-chain amino acid biosynthesis pathway. Importantly, this enzyme is present in bacteria but not in humans, making it an attractive proposition for drug discovery. In the present work, we used molecular docking to identify seventeen potential inhibitors of KARI using an in-house database. Compounds were selected based on docking scores, which were assigned as the result of favourable interactions between the compound and the active site of KARI. The inhibitory constant values for two leads, compounds 14 and 16 are 3.71 and 3.06 µM respectively. To assess the mode of binding, 100 ns molecular dynamics simulations for these two compounds in association with Mt KARI were performed and showed that the complex was stable with an average root mean square deviation of less than 3.5 Å for all atoms. Furthermore, compound 16 showed a minimum inhibitory concentration of 2.06 ± 0.91 µM and a 1.9 fold logarithmic reduction in the growth of Mt in an infected macrophage model. The two compounds exhibited low toxicity against RAW 264.7 cell lines. Thus, both compounds are promising candidates for development as an anti-TB drug leads.