title: Computational Drug Target Screening through Protein Interaction Profiles.
abstract: The development of computational methods to discover novel drug-target interactions on a large scale is of great interest. We propose a new method for virtual screening based on protein interaction profile similarity to discover new targets for molecules, including existing drugs. We calculated Target Interaction Profile Fingerprints (TIPFs) based on ChEMBL database to evaluate drug similarity and generated new putative compound-target candidates from the non-intersecting targets in each pair of compounds. A set of drugs was further studied in monoamine oxidase B (MAO-B) and cyclooxygenase-1 (COX-1) enzyme through molecular docking and experimental assays. The drug ethoxzolamide and the natural compound piperlongumine, present in Piper longum L, showed hMAO-B activity with IC50values of 25 and 65 μM respectively. Five candidates, including lapatinib, SB-202190, RO-316233, GW786460X and indirubin-3'-monoxime were tested against human COX-1. Compounds SB-202190 and RO-316233 showed a IC50in hCOX-1 of 24 and 25 μM respectively (similar range as potent inhibitors such as diclofenac and indomethacin in the same experimental conditions). Lapatinib and indirubin-3'-monoxime showed moderate hCOX-1 activity (19.5% and 28% of enzyme inhibition at 25 μM respectively). Our modeling constitutes a multi-target predictor for large scale virtual screening with potential in lead discovery, repositioning and drug safety.
authors.affiliation: Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA.|Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Vilar
authors.affiliation: CIQUP, Department of Chemistry &Biochemistry, Faculty of Sciences, University of Porto, 4169-007, Porto, Portugal.
authors.forename: Elías
authors.initials: E
authors.lastname: Quezada
authors.affiliation: Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Uriarte
authors.affiliation: Department of Chemistry, American University, 20016 Washington, DC, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Costanzi
authors.affiliation: CIQUP, Department of Chemistry &Biochemistry, Faculty of Sciences, University of Porto, 4169-007, Porto, Portugal.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Borges
authors.affiliation: Department of Pharmacology, CIMUS, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain.
authors.forename: Dolores
authors.initials: D
authors.lastname: Viña
authors.affiliation: Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: George
authors.initials: G
authors.lastname: Hripcsak
mesh_terms: D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry / Q000378:metabolism; D000077341:Lapatinib; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism*; D010091:Oximes / Q000737:chemistry / Q000378:metabolism; D060066:Protein Interaction Maps / Q000187:drug effects; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011799:Quinazolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D011725:Pyridines; D011799:Quinazolines; C474021:indirubin-3'-monoxime; D000077341:Lapatinib; D051545:Cyclooxygenase 1; D008995:Monoamine Oxidase; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole