Binding mode of inhibitors and <i>Cryptosporidium parvum</i> IMP dehydrogenase: A combined ligand- and receptor-based study

<div><p>A combined ligand- and target-based approach was used to analyse the interaction models of <i>Cryptosporidium parvum</i> inosine 5’-monophosphate dehydrogenase (C<i>p</i>IMPDH) with selective inhibitors. First, a ligand-based pharmacophore model was generated from 20 NAD<sup>+</sup> competitive C<i>p</i>IMPDH inhibitors with the HipHop module. The characteristic of the NAD<sup>+</sup> binding site of C<i>p</i>IMPDH 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<sup>+</sup> binding site of C<i>p</i>IMPDH. This research supports the proposal of an interaction model inside the NAD<sup>+</sup> binding site of C<i>p</i>IMPDH, 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 C<i>p</i>IMPDH inhibitors for the treatment of <i>Cryptosporidium</i> infections.</p></div>