posted on 2018-03-16, 00:00authored byAna Trapero, Angela Pacitto, Vinayak Singh, Mohamad Sabbah, Anthony G. Coyne, Valerie Mizrahi, Tom L. Blundell, David B. Ascher, Chris Abell
Tuberculosis (TB)
remains a major cause of mortality worldwide,
and improved treatments are needed to combat emergence of drug resistance.
Inosine 5′-monophosphate dehydrogenase (IMPDH), a crucial enzyme
required for de novo synthesis of guanine nucleotides,
is an attractive TB drug target. Herein, we describe the identification
of potent IMPDH inhibitors using fragment-based screening and structure-based
design techniques. Screening of a fragment library for Mycobacterium
thermoresistible (Mth) IMPDH ΔCBS
inhibitors identified a low affinity phenylimidazole derivative. X-ray
crystallography of the Mth IMPDH ΔCBS–IMP–inhibitor
complex revealed that two molecules of the fragment were bound in
the NAD binding pocket of IMPDH. Linking the two molecules of the
fragment afforded compounds with more than 1000-fold improvement in
IMPDH affinity over the initial fragment hit.