Structure-based discovery of phenyl-diketo acids derivatives as Mycobacterium tuberculosis malate synthase inhibitors

Abstract

Mycobacterium tuberculosis remains one of the most successful bacterial pathogens worldwide. The development of drug-resistant strains and the ability of the bacteria to persist in a latent form in the host are major problems for tuberculosis (TB) control. Glyoxylate shunt is a metabolic bypass of the Krebs cycle and is the key for M. tuberculosis to survive under latent conditions. Malate synthase (MtbMS) catalyzes the second step of the glyoxylate cycle and converts glyoxylate into malate. Phenyl-diketo acid (PDKA) is a potent inhibitor of MtbMS, and its efficacy is validated in a mouse model of TB. To identify novel PDKA analogs as anti-TB compounds, PDKA analogs that obeyed the Lipinski rules (n = 5473) were analyzed and docked with MtbMS structure in three sequential modes. These compounds were then assessed for ADMET parameters. Of the compounds examined, 19 were found to fit well for redocking studies. After optimization, four prospective inhibitors were identified, that along with the reference compound PDKA were subjected to 50 ns molecular dynamics simulation and binding-free energy analyses to evaluate the complex dynamics after ligand binding, the stability of the bound complexes, and the intermolecular interactions between the complexes. The MtbMS-PDKA complex showed the binding free energy of –57.16 kJ·mol⁻¹. After a thorough analysis, our results suggested that three compounds which had binding-free energy of –127.96, −97.60, and –83.98 kJ·mol⁻¹, with PubChem IDs 91937661, 14016246, and 126487337, respectively, have the potential to inhibit MtbMS and can be taken as lead compounds for drug discovery against TB.

Communicated by Ramaswamy H. Sarma

Keywords:

• Mycobacterium tuberculosis
• malate synthase
• virtual screening
• drug target
• molecular dynamics simulation
• phenyl-diketo acid
• molecular docking
• binding energy

Acknowledgements

The authors thank the Sulekor supercomputing facility NEHU installed at Computer Center. RS thanks UGC for providing fellowship, while HS thanks SERB, New Delhi, for providing National Postdoctoral Fellowship (PDF/2017/000458).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Authors’ contributions

RS carried out the experiments and data analysis. TT, HS, and RS conceived the study, participated in its design and coordination. TT and RS wrote the manuscript. All authors read and approved the final manuscript.