Manoj Kumar, Gita Subba Rao, Sujata Sharma, TP Singh, Punit Kaur
Department of Biophysics, All India Institute of Medical Sciences, New Delhi-110029, India.

ABSTRACT

Alarming increase in incidence of drug resistant TB and its synergy with HIV has led the WHO to declare TB as global health problem. The TB drug development initiatives have identified several new anti-mycobacterial drug targets. The enzyme 6-hydroxymethyl-7, 8-dihydropteroate synthase (DHPS) is one such potential drug target. DHPS catalyses the condensation of dihydropteroate pyrophosphate and para-amino benzoic acid (pABA) to form dihydropteroate that is subsequently converted into dihydrofolate, an essential compound for thymidylate synthesis. DHPS is essential for DNA replication in prokaryotes but absent in host and hence is an attractive drug target. It has been exploited as selective drug target for long by sulfa drugs, a structural analogue of pABA. However, single mutations in the DHPS gene lead to resistance against sulfa drugs. We have designed and identified a dipeptide inhibitor using the rational structure based computational approach. Docking studies using CHARMm force field and CDOCKER docking program indicates that identified dipeptide has nanomolar affinity for M.tb DHPS. The dipeptide targets the pterin binding pocket of DHPS as compared to pABA binding pocket by sulfa drugs. The binding to the highly conserved pterin-binding pocket implies that the inhibitor may be less prone to drug resistant mutations. In addition, it has higher affinity for M.tb DHPS as compared to that for the pterin and folate binding pockets of key human proteins. This dipeptide also satisfies all the four Lipinski’s criteria for a small molecule to be drug. Dynamics simulations on a fully hydrated model indicates that the binding of the dipeptide to the M.tb DHPS is stable as the strong binding interactions are retained in the presence of the explicit solvent. The designed dipeptide could be a suitable lead compound for the development of a novel and selective anti-TB drugs.  Read more…