4IXH

Crystal Structure of the Catalytic Domain of the Inosine Monophosphate Dehydrogenase from Cryptosporidium parvum

Summary for 4IXH

• Entry DOI: 10.2210/pdb4ixh/pdb
• Related: 3FFS
• Descriptor: Inosine-5'-monophosphate dehydrogenase, INOSINIC ACID, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: structural genomics, niaid, national institute of allergy and infectious diseases, center for structural genomics of infectious diseases, csgid, alpha-beta fold, tim barrel, oxidoreductase
• Biological source: Cryptosporidium parvum; More
• Cellular location: Cytoplasm : Q8T6T2
• Total number of polymer chains: 4
• Total formula weight: 157366.62

Authors

Kim, Y.,Makowska-Grzyska, M.,Gu, M.,Kavitha, M.,Hedstrom, L.,Anderson, W.F.,Joachimiak, A.,Center for Structural Genomics of Infectious Diseases (CSGID) (deposition date: 2013-01-25, release date: 2013-04-03, Last modification date: 2023-09-20)

Primary citation

Gorla, S.K.,Kavitha, M.,Zhang, M.,Chin, J.E.,Liu, X.,Striepen, B.,Makowska-Grzyska, M.,Kim, Y.,Joachimiak, A.,Hedstrom, L.,Cuny, G.D.
Optimization of Benzoxazole-Based Inhibitors of Cryptosporidium parvum Inosine 5'-Monophosphate Dehydrogenase.
J.Med.Chem., 56:4028-4043, 2013

PubMed Abstract: Cryptosporidium parvum is an enteric protozoan parasite that has emerged as a major cause of diarrhea, malnutrition, and gastroenteritis and poses a potential bioterrorism threat. C. parvum synthesizes guanine nucleotides from host adenosine in a streamlined pathway that relies on inosine 5'-monophosphate dehydrogenase (IMPDH). We have previously identified several parasite-selective C. parvum IMPDH (CpIMPDH) inhibitors by high-throughput screening. In this paper, we report the structure-activity relationship (SAR) for a series of benzoxazole derivatives with many compounds demonstrating CpIMPDH IC50 values in the nanomolar range and >500-fold selectivity over human IMPDH (hIMPDH). Unlike previously reported CpIMPDH inhibitors, these compounds are competitive inhibitors versus NAD(+). The SAR study reveals that pyridine and other small heteroaromatic substituents are required at the 2-position of the benzoxazole for potent inhibitory activity. In addition, several other SAR conclusions are highlighted with regard to the benzoxazole and the amide portion of the inhibitor, including preferred stereochemistry. An X-ray crystal structure of a representative E·IMP·inhibitor complex is also presented. Overall, the secondary amine derivative 15a demonstrated excellent CpIMPDH inhibitory activity (IC50 = 0.5 ± 0.1 nM) and moderate stability (t1/2 = 44 min) in mouse liver microsomes. Compound 73, the racemic version of 15a, also displayed superb antiparasitic activity in a Toxoplasma gondii strain that relies on CpIMPDH (EC50 = 20 ± 20 nM), and selectivity versus a wild-type T. gondii strain (200-fold). No toxicity was observed (LD50 > 50 μM) against a panel of four mammalian cells lines.

PubMed: 23668331
DOI: 10.1021/jm400241j

Experimental method

X-RAY DIFFRACTION (2.105 Å)