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

Abstract

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 (<i>menG</i>) 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 <i>menG</i>. This study investigated the structural and dynamic impacts of DG70 upon binding to <i>menG</i> using atom-based dynamic simulation. Our findings revealed that the modeled structure of <i>menG</i> 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, <i>etc.</i> 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-<i>menG</i> structure. However, in the DG70-<i>menG</i>, 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 <i>menG</i> protein. Conclusively, insights from this study, highlight the structural "Achilles heel" in <i>menG</i> protein which can be further leveraged by inhibitors tailored to specifically target them.