5OU2

M. thermoresistible IMPDH in complex with IMP and Compound 2 (NMR744)

Summary for 5OU2

• Entry DOI: 10.2210/pdb5ou2/pdb
• Descriptor: Inosine-5'-monophosphate dehydrogenase,Inosine-5'-monophosphate dehydrogenase, INOSINIC ACID, 4-(4-bromophenyl)-1H-imidazole, ... (4 entities in total)
• Functional Keywords: complex, fragment, impdh, oxidoreductase
• Biological source: Mycobacterium thermoresistibile (strain ATCC 19527 / DSM 44167 / CIP 105390 / JCM 6362 / NCTC 10409 / 316); More
• Total number of polymer chains: 1
• Total formula weight: 40648.82

Authors

Ascher, D.B.,Pacitto, A.,Blundell, T.L. (deposition date: 2017-08-23, release date: 2018-03-28, Last modification date: 2024-05-08)

Primary citation

Trapero, A.,Pacitto, A.,Singh, V.,Sabbah, M.,Coyne, A.G.,Mizrahi, V.,Blundell, T.L.,Ascher, D.B.,Abell, C.
Fragment-Based Approach to Targeting Inosine-5'-monophosphate Dehydrogenase (IMPDH) from Mycobacterium tuberculosis.
J. Med. Chem., 61:2806-2822, 2018

PubMed 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. Linking the two molecules of the fragment afforded compounds with more than 1000-fold improvement in IMPDH affinity over the initial fragment hit.

PubMed: 29547284
DOI: 10.1021/acs.jmedchem.7b01622

Experimental method

X-RAY DIFFRACTION (1.45 Å)