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A fragment-based approach to targeting inosine-5´-monophosphate dehydrogenase (IMPDH) from Mycobacterium tuberculosis

DOI: 10.1021/acs.jmedchem.7b01622 DOI Help

Authors: Ana Trapero (University of Cambridge) , Angela Pacitto (University of Cambridge) , Vinayak Singh (University of Cape Town) , Mohamad Sabbah (University of Cambridge) , Anthony G. Coyne (University of Cambridge) , Valerie Mizrahi (University of Cape Town) , Tom L. Blundell (University of Cambridge) , David B. Ascher (University of Cambridge; University of Melbourne) , Chris Abell (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: March 2018

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 the NAD binding pocket of IMPDH. The linking the two molecules of the fragment afforded compounds with more than 1000-fold improvement in IMPDH affinity over the initial fragment hit.

Journal Keywords: IMPDH; Mycobacterium tuberculosis; fragment-based drug discovery; 2-acylaminoimidazole derivatives; X-ray crystallography

Subject Areas: Biology and Bio-materials, Medicine