Journal article
Fragment-Based Approach to Targeting Inosine-5′-monophosphate Dehydrogenase (IMPDH) from Mycobacterium tuberculosis
A Trapero, A Pacitto, V Singh, M Sabbah, AG Coyne, V Mizrahi, TL Blundell, DB Ascher, C Abell
Journal of Medicinal Chemistry | AMER CHEMICAL SOC | Published : 2018
Open access
Abstract
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..
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Awarded by National Research Foundation of Korea
Funding Acknowledgements
This work was supported by the Bill and Melinda Gates Foundation (Hit-TB) and FP7 European Project MM4TB Grant no. 260872. D.B.A was supported by a C. J. Martin Research Fellowship from the National Health and Medical Research Council of Australia (APP1072476) and the Jack Brockhoff Foundation (JBF 4186, 2016). D.B.A. and T.L.B. were also funded by a Newton Fund RCUK-CONFAP Grant awarded by The Medical Research Council and Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (MR/M026302/1). V.M. and V.S. were also supported by grants from the HHMI (Senior International Research Scholars grant to V.M.), the South African Medical Research Council, and the National Research Foundation.