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First-in-class allosteric inhibitors of bacterial IMPDHs

Abstract : 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.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-02125232
Contributor : Hélène Munier-Lehmann <>
Submitted on : Friday, May 10, 2019 - 11:41:27 AM
Last modification on : Monday, January 13, 2020 - 5:08:16 PM

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Thomas Alexandre, Alexandru Lupan, Olivier Helynck, Sophie Vichier-Guerre, Laurence Dugué, et al.. First-in-class allosteric inhibitors of bacterial IMPDHs. European Journal of Medicinal Chemistry, Elsevier, 2019, 167, pp.124-132. ⟨10.1016/j.ejmech.2019.01.064⟩. ⟨pasteur-02125232⟩

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