PDBsum entry 4ixh

Oxidoreductase

PDB id: 4ixh

Contents

Protein chains

336 a.a.

Ligands

IMP ×4

EDO ×5

Q21 ×4

Waters ×486

PDB id:

4ixh

Name:

Oxidoreductase

Title:

Crystal structure of the catalytic domain of the inosine monophosphate dehydrogenase from cryptosporidium parvum

Structure:

Inosine-5'-monophosphate dehydrogenase. Chain: a, b, c, d. Synonym: imp dehydrogenase, impd, impdh. Engineered: yes

Source:

Cryptosporidium parvum. Organism_taxid: 5807. Gene: 56k.02, cgd6_20. Expressed in: escherichia coli. Expression_system_taxid: 511693.

Resolution:

2.11Å R-factor: 0.164 R-free: 0.210

Authors:

Y.Kim,M.Makowska-Grzyska,M.Gu,M.Kavitha,L.Hedstrom,W.F.Anderson, A.Joachimiak,Center For Structural Genomics Of Infectious Diseases (Csgid)

Key ref:

S.K.Gorla et al. (2013). Optimization of benzoxazole-based inhibitors of Cryptosporidium parvum inosine 5'-monophosphate dehydrogenase. J Med Chem, 56, 4028-4043. PubMed id: 23668331 DOI: 10.1021/jm400241j

Date:

25-Jan-13 Release date: 03-Apr-13

Protein chains

Q8T6T2  (IMDH_CRYPV) -  Inosine-5'-monophosphate dehydrogenase from Cryptosporidium parvum

Seq: 400 a.a.

Struc: 336 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.1.1.1.205 - Imp dehydrogenase.
• Pathway: AMP and GMP Biosynthesis
• Reaction: IMP + NAD⁺ + H2O = XMP + NADH + H⁺

IMP + NAD(+) (Bound ligand (Het Group name = IMP) corresponds exactly) + H2O = XMP + NADH + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/jm400241j

J Med Chem 56:4028-4043 (2013)

PubMed id: 23668331

Optimization of benzoxazole-based inhibitors of Cryptosporidium parvum inosine 5'-monophosphate dehydrogenase.

S.K.Gorla, M.Kavitha, M.Zhang, J.E.Chin, X.Liu, B.Striepen, M.Makowska-Grzyska, Y.Kim, A.Joachimiak, L.Hedstrom, G.D.Cuny.

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.