Screening and reckoning of potential therapeutic agents against DprE1 protein of Mycobacterium tuberculosis

Abstract

Tuberculosis is caused by Mycobacterium tuberculosis, a resilient microbe that can survive within the long courses of medications as well as several years of dormancy in the host system. Although tuberculosis is a preventable and curable disease, however, the rise of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) have made remedy more difficult and a major concern to public health. In Mycobacterium tuberculosis, DprE1 is a key isomerase enzyme that has a vital function in cell wall synthesis. Moreover, DprE1 has also been recognized as a crucial target for drug development against tuberculosis. In the present study, molecular docking, dynamics simulations, and thermodynamic free energy calculations were used to analyze the ability of aminoarylbenzosuberene (AAB) molecules to inhibit DprE1 in comparison to six co-crystallized DprE1 inhibitors. This study identified a promising molecule (AAB4) with better stability and binding affinity than the co-crystallized inhibitors. Moreover, AAB4 molecule could also inhibit (Y314C)-DprE1 protein (a TCA1 inhibitor resistance mutant). Thus, the molecule AAB4 could be used as potential lead against tuberculosis and would be an easy pick for in-vitro and in-vivo studies.