4IXH

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

4IXH の概要

• エントリーDOI: 10.2210/pdb4ixh/pdb
• 関連するPDBエントリー: 3FFS
• 分子名称: Inosine-5'-monophosphate dehydrogenase, INOSINIC ACID, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: structural genomics, niaid, national institute of allergy and infectious diseases, center for structural genomics of infectious diseases, csgid, alpha-beta fold, tim barrel, oxidoreductase
• 由来する生物種: Cryptosporidium parvum; 詳細
• 細胞内の位置: Cytoplasm : Q8T6T2
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 157366.62

構造登録者

Kim, Y.,Makowska-Grzyska, M.,Gu, M.,Kavitha, M.,Hedstrom, L.,Anderson, W.F.,Joachimiak, A.,Center for Structural Genomics of Infectious Diseases (CSGID) (登録日: 2013-01-25, 公開日: 2013-04-03, 最終更新日: 2023-09-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.105 Å)