title: Virtual Screening for Transition State Analogue Inhibitors of IRAP Based on Quantum Mechanically Derived Reaction Coordinates.
abstract: Transition state and high energy intermediate mimetics have the potential to be very potent enzyme inhibitors. In this study, a model of peptide hydrolysis in the active site of insulin-regulated aminopeptidase (IRAP) was developed using density functional theory calculations and the cluster approach. The 3D structure models of the reaction coordinates were used for virtual screening to obtain new chemical starting points for IRAP inhibitors. This mechanism-based virtual screening process managed to identify several known peptidase inhibitors from a library of over 5 million compounds, and biological testing identified one compound not previously reported as an IRAP inhibitor. This novel methodology for virtual screening is a promising approach to identify new inhibitors mimicking key transition states or intermediates of an enzymatic reaction.
authors.affiliation: Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, BMC, Uppsala University , P.O. Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Svensson
authors.affiliation: Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, BMC, Uppsala University , P.O. Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Engen
authors.affiliation: Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet , Tomtebodavägen 23A, SE-171 65 Solna, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lundbäck
authors.affiliation: Science for Life Laboratory, Department of Medicinal Chemistry, BMC, Uppsala University , P.O. Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Larhed
authors.affiliation: Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, BMC, Uppsala University , P.O. Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: Sköld
mesh_terms: D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D003412:Cricetulus; D010122:Cystinyl Aminopeptidase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D011789:Quantum Theory; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase