Selective Inhibitor Design against Thymidylate Synthase of <i>Mycobacterium tuberculosis</i> Using Alchemical Simulations.

ABSTRACT: Thymidylate synthase is an essential enzyme that catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Thymidylate synthase from Mycobacterium tuberculosis(MtbThyX) recognizes the deprotonated substrate dUMP^(d) (ionized at N3, charge = -3) involving the cationic side chain of Arg199, whereas the human analogue (hThyA) selects the natural substrate dUMP (charge = -2) by involving the polar side chain of Asn226 in the binding pocket. Distinctly different protonation states of the substrate and the catalytic pocket architecture make MtbThyX an attractive drug target for combating Mycobacterium tuberculosis. Fluorodeoxyuridylate (FdUMP) is a known inhibitor of thymidylate synthase, which is severely limited by poor select

SUBMITTER: Sengupta P 

PROVIDER: S-EPMC12004180 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature