Mycophenolic anilides as broad specificity inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitors. Issue 24 (15th December 2020)

• Record Type: Journal Article
• Authors: Lee, Seungheon; Ku, Angela F.; Vippila, Mohana Rao; Wang, Yong; Zhang, Minjia; Wang, Xingyou; Hedstrom, Lizbeth; Cuny, Gregory D.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 24(2020)
• Publication Date: 2020-12-15
• Subjects: Cryptosporidium parvum -- IMPDH -- Inosine-5'-monophosphate dehydrogenase -- Inhibitor -- Binding mode; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127543
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Inosine-5′-monophosphate dehydrogenase (IMPDH) is a potential target for microorganisms. However, identifying inhibitor design determinants for IMPDH orthologs continues to evolve. Herein, a series of mycophenolic anilide inhibitors of Cryptosporidium parvum and human IMPDHs are reported. Furthermore, molecular docking of 12 (e.g. SH-19; Cp IMPDH K i, app = 0.042 ± 0.015 µM, Hs IMPDH2 K i, app = 0.13 ± 0.05 µM) supports different binding modes with the two enzymes. For Cp IMPDH the inhibitor extends into a pocket in an adjacent subunit. In contrast, docking suggests the inhibitor interacts with Ser276 in the NAD binding site in Hs IMPDH2, as well as an adjacent pocket within the same subunit. These results provide further guidance for generating IMPDH inhibitors for enzymes found in an array of pathogenic microorganisms, including Mycobacterium tuberculosis .