First-in-class allosteric inhibitors of bacterial IMPDHs

• Published in: European journal of medicinal chemistry Vol. 167; pp. 124 - 132
• Main Authors: Alexandre, Thomas, Lupan, Alexandru, Helynck, Olivier, Vichier-Guerre, Sophie, Dugué, Laurence, Gelin, Muriel, Haouz, Ahmed, Labesse, Gilles, Munier-Lehmann, Hélène
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01-04-2019; Elsevier
• Subjects: Adenosine Triphosphate; Allosteric inhibitor; Allosteric Regulation; Apoproteins; Bacterial Proteins; Bacteriology; Bateman domain; Biochemistry, Molecular Biology; Chemical library screening; Chemical Sciences; Enzyme Inhibitors; IMP Dehydrogenase; IMPDH; Life Sciences; Medicinal Chemistry; Microbiology and Parasitology; Nucleotide metabolism; Organic chemistry; Protein Domains; Quaternary structure; Small Molecule Libraries; IMPDH; Allosteric inhibitor; Chemical library screening; Bateman domain; Nucleotide metabolism; Quaternary structure
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.01.064

Inosine-5‘-monophosphate dehydrogenase (IMPDH) is an essential enzyme in many bacterial pathogens and is considered as a potential drug target for the development of new antibacterial agents. Our recent work has revealed the crucial role of one of the two structural domains (i.e. Bateman domain) in the regulation of the quaternary structure and enzymatic activity of bacterial IMPDHs. Thus, we have screened chemical libraries to search for compounds targeting the Bateman domain and identified first in-class allosteric inhibitors of a bacterial IMPDH. These inhibitors were shown to counteract the activation by the natural positive effector, MgATP, and to block the enzyme in its apo conformation (low affinity for IMP). Our structural studies demonstrate the versatility of the Bateman domain to accommodate totally unrelated chemical scaffolds and pave the way for the development of allosteric inhibitors, an avenue little explored until now.
[Display omitted]
•Four chemical series identified as novel allosteric IMPDH inhibitors by HTS.•Original binding mode in the Bateman domain solved by X-ray structure.•First in-class inhibitors trap IMPDH in its apo conformation.