title: In silico design of human IMPDH inhibitors using pharmacophore mapping and molecular docking approaches.
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.
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Rui-Juan
authors.initials: RJ
authors.lastname: Li
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 10050, China.
authors.forename: Ya-Li
authors.initials: YL
authors.lastname: Wang
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Qing-He
authors.initials: QH
authors.lastname: Wang
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Mao-Sheng
authors.initials: MS
authors.lastname: Cheng
mesh_terms: D000465:Algorithms; D016208:Databases, Factual; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006151:Guanosine; D006801:Humans; D006860:Hydrogen Bonding; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D008024:Ligands; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D015203:Reproducibility of Results
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D006151:Guanosine; D007168:IMP Dehydrogenase; C488211:IMPDH1 protein, human