In silico design of human IMPDH inhibitors using pharmacophore mapping and molecular docking approaches.

Rui-Juan Li,Qing-He Wang,Jian Wang,Mao-Sheng Cheng,Ya-Li Wang

doi:10.1155/2015/418767

Abstract

Inosine 5′-monophosphate dehydrogenase (IMPDH) is one of the crucial enzymes in the de novo biosynthesis of guanosine nucleotides. It has served as an attractive target in immunosuppressive, anticancer, antiviral, and antiparasitic therapeutic strategies. In this study, pharmacophore mapping and molecular docking approaches were employed to discover novel Homo sapiens IMPDH (hIMPDH) inhibitors. The Güner-Henry (GH) scoring method was used to evaluate the quality of generated pharmacophore hypotheses. One of the generated pharmacophore hypotheses was found to possess a GH score of 0.67. Ten potential compounds were selected from the ZINC database using a pharmacophore mapping approach and docked into the IMPDH active site. We find two hits (i.e., ZINC02090792 and ZINC00048033) that match well the optimal pharmacophore features used in this investigation, and it is found that they form interactions with key residues of IMPDH. We propose that these two hits are lead compounds for the development of novel hIMPDH inhibitors.

Highlights

Inosine 5󸀠-monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme in the de novo synthesis of guanine nucleotides
A decoy database, which was used for pharmacophore identification and validation, was constructed to include 20 independent active Homo sapiens IMPDH (hIMPDH) inhibitors, 9 inactive hIMPDH inhibitors, and 700 inactive ligands from the ZINC database
We have established a ligand-based pharmacophore model followed by virtual screening and molecular docking studies to discover novel hIMPDH inhibitors

Summary

Introduction

Inosine 5󸀠-monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme in the de novo synthesis of guanine nucleotides. It catalyzes the conversion of inosine 5󸀠-monophosphate (IMP) to xanthosine 5󸀠-monophosphate (XMP) [1, 2] and plays an important role in the regulation of cell growth [3]. Gene sequence variation in the hIMPDH2 gene may contribute to the large interindividual difference of baseline hIMPDH enzyme activity, immunosuppressive efficacy, and side effects in transplant recipients receiving mycophenolic acid [9,10,11]. Inhibition of hIMPDH2 has become an important strategy in the treatment of diseases related to immunosuppression, cancer, and viral and parasitic infections [12,13,14,15,16]. It has long been the belief that chemotherapy would be improved with selective inhibition of hIMPDH2, this view has recently been challenged by the surprising observation that hIMPDH1 is an antiangiogenic target [17]

Methods

Results

Conclusion