Identification of peptidomimetic compounds as potential inhibitors against MurA enzyme of Mycobacterium tuberculosis

Abstract

Increasing prevalence of resistance to anti-tubercular drugs has become the foremost challenge now. According to WHO, over half a million of multidrug resistance cases (rifampicin, isoniazid, etc.) were reported in 2017, mostly emerging from countries such as China, India, and Russia. Therefore, developing new drugs or repurposing existing ones is need of the hour. The Mycobacterium cell wall biogenesis pathway offers many attractive targets for drug discovery against Tuberculosis (TB). MurA, a transferase enzyme that catalyzes the initial step of peptidoglycan (PG) biosynthesis, is one among them. A peptidoglycan layer resides over the plasma membrane and is an integral component of the bacterial cell wall. Therefore, disruption of their formation through inhibition of MurA enzyme should lead to deficiency in Mycobacterium cell synthesis. Based on this strategy, we have designed this study where two libraries of peptidomimetic compounds (Asinex & ChemDiv) were first screened against our modeled MurA structure and then validated through molecular dynamic simulations. From our virtual screening, top four compounds (ChemDiv: D675-0102, D675-0217; Asinex: BDE25373574, BDE 26717803) were selected based on their docking scores, binding energies, and interactions with catalytic site residues, for further evaluation. Results revealed stable ligand-MurA interactions throughout 50 ns of MD simulation and also druggability acceptable pharmacokinetic profile for all four compounds. Thus, based on our findings, these compounds could be considered as potential inhibitors of Mycobacterium MurA enzyme and hence be further tested for in vitro experimental validation as TB therapeutic drug candidate.

Communicated by Ramaswamy H. Sarma

Keywords:

• Mycobacterium tuberculosis
• MurA
• peptidomimetic
• molecular docking
• simulations

Acknowledgements

RG and PK would like to thank IIT Mandi for administrative support. KUS would like to acknowledge ICMR for senior research fellowship. RG is thankful for the funding support by the Department of Biotechnology, Govt. of India (BT/IN/IC-Impacts/21/DS/2016-2017). We would like to thank Mr. Pritesh Bhatt for his kind support from Schrodinger company.

Disclosure statement

All authors affirm that there are no conflicts of interests.

Additional information

Notes on contributors

Prateek Kumar

RG: Conception and design; PK, KUS, and RG: acquisition of data, analysis, and writing of the manuscript.

Kumar Udit Saumya

RG: Conception and design; PK, KUS, and RG: acquisition of data, analysis, and writing of the manuscript.

Rajanish Giri

RG: Conception and design; PK, KUS, and RG: acquisition of data, analysis, and writing of the manuscript.