Computational design of a new inhibitor for 6-Hydroxymethyl-7,8-dihydropteroate synthase from Mycobacterium tuberculosis

Abstract

Tuberculosis that is caused by Mycobacterium tuberculosis is one of the widespread infectious diseases with millions of death worldwide. Prevalence of Multi-drug-resistant (MDR) tuberculosis and emergence of extensively drug-resistant (XDR) species of M. tuberculosis have necessitated the discovery of new and potent antibiotics. Designing of specific inhibitors for 6-hydroxymethyl-7,8-dihydropteroate synthase (DHPS) has attracted a great interest because of its crucial role in de novo folate synthesis in prokaryotic but not in mammalian cells. In the current study, the ligand of DHPS, namely 6-hydroxymethylpterin monophosphate (PtP) was used as a template for structural-based inhibitor design. Virtual screening was performed between compounds with structural similarity to PtP. Between docked compounds against DHPS, 2-amino-6-(1,2,3-trihydroxybutyl)-1H-pteridin-4-one (PtP_1) showed the most negative free energy of binding. Binding of PtP and PtP_1 to DHPS was further investigated through molecular dynamic simulation. DHPS as alone or in complex with ligands was minimized, solvated in an explicit water cage, neutralized by addition of required ions and simulated for 50 ns. According to trajectories, PtP_1 shows high affinity for the active site of DHPS by H-bonds, hydrophobic forces, and cation-? interactions. Our results show that there could be a great chance for designing new inhibitors against DHPS from M. tuberculosis .