Thompson loop: opportunities for antitubercular drug design by targeting the weak spot in demethylmenaquinone...

Drug-resistant Tuberculosis (TB) has remained the top global health challenge, with a yearly estimation of 10 million infections and 1.5 million deaths in humans. Demethylmenaquinone methyltransferase (menG) catalyzes demethylmenaquinone conversion to menaquinone (MK) that is implicated in the TB pathogenesis, hence, it has become a major drug target. DG70 is a biphenyl amide compound known to be a high binding affinity inhibitor of menG. This study investigated the structural and dynamic impacts of DG70 upon binding to menG using atom-based dynamic simulation. Our findings revealed that the modeled structure of menG possesses some Rossman-like methyltransferase characteristic features including two GXG motifs, an omega-like loop (residues 210-220) called the Thompson loop, nine α-helices, five β-strands, etc. Furthermore, atom-based dynamic simulations revealed that the Thompson loop is critical in the therapeutic activity of DG70. The loop assumed an open conformation in the unliganded-menG structure. However, in the DG70-menG, it assumed a tightly closed conformation. This explains the high binding affinity (-32.48 kcal mol^-1) observed in the energy calculations. Interestingly, these findings are further collaborated by the conformational perturbation in the menG protein. Conclusively, insights from this study, highlight the structural "Achilles heel" in menG protein which can be further leveraged by inhibitors tailored to specifically target them.