A Three‐Dimensional Pharmacophore Model for IMPDH Inhibitors

Abstract

Inosine 5'-monophosphate dehydrogenase (IMPDH) is a key enzyme in the de novo synthesis of guanosine nucleotides. It is considered an important target in the quest for drugs in the immunosuppressive, antiviral, antibacterial and anticancer therapeutic areas. In this study, a chemical feature-based pharmacophore model of IMPDH inhibitors has been firstly developed with the aid of the HypoRefine protocol within Discovery Studio 2.5. The best model for IMPDH inhibitors, Hypo1-1, was characterized by the best correlation coefficient (0.97595) and the lowest RMSD (0.582058). It consisted of one hydrogen-bond donor, one hydrogen-bond acceptor, one aromatic ring and one hydrophobic feature, as well as two excluded volumes. The model was validated using a wide range of test molecules and a cross-validation. Furthermore, the pharmacophore features were confirmed by molecular docking studies. The pharmacophore model could quantitatively predict inhibitor activity and identify highly potent molecules. Therefore, the present results could be valuable for the discovery and development of specific IMPDH inhibitors.

Evaluation of Bronopol and Disulfiram as Potential Candidatus Liberibacter asiaticus Inosine 5′-Monophosphate Dehydrogenase Inhibitors by Using Molecular Docking and Enzyme Kinetic

“…Homology modeling and in silico docking were performed to study the structure-activity relationship of indole derivatives against Helicobacter pylori IMPDH [63]. The crystal structure of IMPDH from Cricetulus griseus was prepared by using Discovery Studio 2.5 to build a pharmacophore model of IMPDH inhibitors and for the in silico docking analysis [64]. These studies supported the feasibility of molecular docking.…”

Design, synthesis and biological evaluation of novel inosine 5′-monophosphate dehydrogenase (IMPDH) inhibitors

“…Three out of five features [acceptor (A), hydrophobic (H) and ring (R)] resided in Part A of 3, whereas Parts B and C each contained one feature, a donor (D) and an acceptor (A), respectively ( Figure 2). The first part of our study was to find a suitable replacement for 4-cyano-3-methoxyphenyl (Part A) substructure which would possess corresponding pharmacophoric features A, H and R. These modifications (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)) are listed in Table 1 …”

“…Recently, a chemical feature-based pharmacophore model of IMPDH inhibitors consisting of six features (one H-bond donor, one H-bond acceptor, one aromatic ring, one hydrophobic and two excluded volumes) appeared in the literature 14 . Further, the pharmacophore features were confirmed by molecular docking analyses.…”

Inosine 5′-Monophosphate Dehydrogenase Inhibitors as Antimicrobial Agents: Recent Progress and Future Perspectives

“…Five compounds bind only in the nicotinamide portion of the NAD + -site, whereas three extend from the nicotinamide site into the adenosine subsite. Four compounds displayed antiparasitic activity (44,(49)(50)(51), further validating IMPDH as a target against cryptosporidiosis. Significantly, the inhibitors were found to be more potent than paromomycin.…”

“…Selection of the structurally diverse ligands and cross-validation are the key determinants of the successful outcome of the developed models [44]. Recently, a chemical feature-based pharmacophore model of IMPDH inhibitors consisting of six features (one H-bond donor, one H-bond acceptor, one aromatic ring, one hydrophobic and two excluded volumes) was reported [44]. Extensive validation of the developed model was done using several test molecules and crossvalidation.…”