Structure of Cryptosporidium IMP Dehydrogenase Bound to an Inhibitor with in Vivo Antiparasitic Activity

Overview

Journal Acta Crystallogr F Struct Biol Commun

Specialty Chemistry

Date 2015 May 7

PMID 25945705

Citations 4

Authors

Youngchang Kim

Magdalena Makowska-Grzyska

Suresh Kumar Gorla

Deviprasad R Gollapalli

Gregory D Cuny

Andrzej Joachimiak

Lizbeth Hedstrom

Affiliations

Soon will be listed here.

Abstract

Inosine 5'-monophosphate dehydrogenase (IMPDH) is a promising target for the treatment of Cryptosporidium infections. Here, the structure of C. parvum IMPDH (CpIMPDH) in complex with inosine 5'-monophosphate (IMP) and P131, an inhibitor with in vivo anticryptosporidial activity, is reported. P131 contains two aromatic groups, one of which interacts with the hypoxanthine ring of IMP, while the second interacts with the aromatic ring of a tyrosine in the adjacent subunit. In addition, the amine and NO2 moieties bind in hydrated cavities, forming water-mediated hydrogen bonds to the protein. The design of compounds to replace these water molecules is a new strategy for the further optimization of C. parvum inhibitors for both antiparasitic and antibacterial applications.

Citing Articles

Role of the Mobile Active Site Flap in IMP Dehydrogenase Inhibitor Binding.

Wang X, Rosenberg M, Kim Y, Maltseva N, Cuny G, Joachimiak A ACS Infect Dis. 2025; 11(2):442-452.

PMID: 39879323 PMC: 11841048. DOI: 10.1021/acsinfecdis.4c00636.

The Enzymatic Activity of Inosine 5'-Monophosphate Dehydrogenase May Not Be a Vulnerable Target for Infections.

Modi G, Marqus G, Vippila M, Gollapalli D, Kim Y, Manna A ACS Infect Dis. 2021; 7(11):3062-3076.

PMID: 34590817 PMC: 9575405. DOI: 10.1021/acsinfecdis.1c00342.

Mycophenolic anilides as broad specificity inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitors.

Lee S, Ku A, Vippila M, Wang Y, Zhang M, Wang X Bioorg Med Chem Lett. 2020; 30(24):127543.

PMID: 32931912 PMC: 9511823. DOI: 10.1016/j.bmcl.2020.127543.

Inhibitors of inosine 5'-monophosphate dehydrogenase as emerging new generation antimicrobial agents.

Juvale K, Shaik A, Kirubakaran S Medchemcomm. 2019; 10(8):1290-1301.

PMID: 31534651 PMC: 6727467. DOI: 10.1039/c9md00179d.

The Inosine Monophosphate Dehydrogenase, GuaB2, Is a Vulnerable New Bactericidal Drug Target for Tuberculosis.

Singh V, Donini S, Pacitto A, Sala C, Hartkoorn R, Dhar N ACS Infect Dis. 2016; 3(1):5-17.

PMID: 27726334 PMC: 5241705. DOI: 10.1021/acsinfecdis.6b00102.

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