title: Prediction of off-target effects on angiotensin-converting enzyme 2.
abstract: The authors describe a structure-based strategy to identify therapeutically beneficial off-target effects by screening a chemical library of Food and Drug Administration (FDA)-approved small-molecule drugs matching pharmacophores defined for specific target proteins. They applied this strategy to angiotensin-converting enzyme 2 (ACE2), an enzyme that generates vasodilatory peptides and promotes protection from hypertension-associated cardiovascular disease. The conformation-based structural selection method by molecular docking using DOCK allowed them to identify a series of FDA-approved drugs that enhance catalytic efficiency of ACE2 in vitro. These data demonstrate that libraries of approved drugs can be rapidly screened to identify potential side effects due to interactions with specific proteins other than the intended targets.
authors.affiliation: Department of Chemistry, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Lidia V
authors.initials: LV
authors.lastname: Kulemina
authors.forename: David A
authors.initials: DA
authors.lastname: Ostrov
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000085962:Angiotensin-Converting Enzyme 2; D002851:Chromatography, High Pressure Liquid; D004133:Diminazene / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects*; D057166:High-Throughput Screening Assays; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D007700:Kinetics; D008958:Models, Molecular; D010455:Peptides / Q000032:analysis / Q000737:chemistry; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry / Q000378:metabolism*; D055553:Prescription Drugs / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013379:Substrate Specificity; D013816:Thermodynamics; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D010455:Peptides; D055553:Prescription Drugs; D054852:Small Molecule Libraries; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2; D004133:Diminazene