title: Binding mode of inhibitors and Cryptosporidium parvum IMP dehydrogenase: A combined ligand- and receptor-based study.
abstract: A combined ligand- and target-based approach was used to analyse the interaction models of Cryptosporidium parvum inosine 5'-monophosphate dehydrogenase (CpIMPDH) with selective inhibitors. First, a ligand-based pharmacophore model was generated from 20 NAD(+) competitive CpIMPDH inhibitors with the HipHop module. The characteristic of the NAD(+) binding site of CpIMPDH was then described, and the binding modes of the representative inhibitors were studied by molecular docking. The combination of the pharmacophore model and the docking results allowed us to evaluate the pharmacophore features and structural information of the NAD(+) binding site of CpIMPDH. This research supports the proposal of an interaction model inside the NAD(+) binding site of CpIMPDH, consisting of four key interaction points: two hydrophobic-aromatic groups, a hydrophobic-aliphatic group and a hydrogen bond donor. This study also provides guidance for the design of more potent CpIMPDH inhibitors for the treatment of Cryptosporidium infections.
authors.affiliation: a Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education , Shenyang Pharmaceutical University , Shenyang , China.
authors.forename: R-J
authors.initials: RJ
authors.lastname: Li
authors.forename: Y-L
authors.initials: YL
authors.lastname: Wang
authors.forename: Q-H
authors.initials: QH
authors.lastname: Wang
authors.forename: W-X
authors.initials: WX
authors.lastname: Huang
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: M-S
authors.initials: MS
authors.lastname: Cheng
mesh_terms: D000977:Antiparasitic Agents / Q000737:chemistry*; D001665:Binding Sites; D016785:Cryptosporidium parvum / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008024:Ligands; D062105:Molecular Docking Simulation; D009243:NAD / Q000737:chemistry; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000977:Antiparasitic Agents; D004791:Enzyme Inhibitors; D008024:Ligands; D015800:Protozoan Proteins; D009243:NAD; D007168:IMP Dehydrogenase
keywords: IMPDH; cryptosporidium parvum; inhibitors; molecular docking; pharmacophore modelling