title: A comparative study of AutoDock and PMF scoring performances, and SAR of 2-substituted pyrazolotriazolopyrimidines and 4-substituted pyrazolopyrimidines as potent xanthine oxidase inhibitors.
abstract: 4-Alkylidenehydrazino-1H-pyrazolo[3,4-d]pyrimidines, 4-arylmethylidenehydrazino-1H-pyrazolo[3,4-d]pyrimidines, and 2-substituted 7H-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]-pyrimidines as potential xanthine oxidase inhibitors were docked into the active site of the bovine milk xanthine dehydrogenase using two scoring functions involved in AutoDock 3.05 and the CAChe 6.1.10. The correlation coefficiency obtained between the AutoDock binding energy and IC(50) of the inhibitors was better than that obtained by the CAChe-PMF docking score. Many ligands exhibited one to four hydrogen bonds within the active site, where the detected hydrogen bonds by CAChe was identified quantitatively in the docked conformation by using MOPAC 2002. These ligands were docked into a long, narrow channel of the enzyme leading to the molybdopterin active moiety, with hydrogen bonding and electrostatic interaction between the planar aromatic moiety of the ligand and the enzyme. Furthermore, SAR among inhibitors was investigated, which revealed that the oxo group of pyrazolopyrimidine analogs is essential for its activity and the tricyclic derivatives are shown to be more potent than bicyclic ones. The mode of interaction of the docked inhibitors was described in details.
authors.affiliation: Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan.
authors.forename: Hamed I
authors.initials: HI
authors.lastname: Ali
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fujita
authors.forename: Eiichi
authors.initials: E
authors.lastname: Akaho
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Nagamatsu
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D002417:Cattle; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C031280:pyrazole; D014969:Xanthine Oxidase; C030986:pyrimidine