title: Molecular basis of cyclooxygenase enzymes (COXs) selective inhibition.
abstract: The widely used nonsteroidal anti-inflammatory drugs block the cyclooxygenase enzymes (COXs) and are clinically used for the treatment of inflammation, pain, and cancers. A selective inhibition of the different isoforms, particularly COX-2, is desirable, and consequently a deeper understanding of the molecular basis of selective inhibition is of great demand. Using an advanced computational technique we have simulated the full dissociation process of a highly potent and selective inhibitor, SC-558, in both COX-1 and COX-2. We have found a previously unreported alternative binding mode in COX-2 explaining the time-dependent inhibition exhibited by this class of inhibitors and consequently their long residence time inside this isoform. Our metadynamics-based approach allows us to illuminate the highly dynamical character of the ligand/protein recognition process, thus explaining a wealth of experimental data and paving the way to an innovative strategy for designing new COX inhibitors with tuned selectivity.
authors.affiliation: Computational Science, Department of Chemistry and Applied Biosciences, Eidgenössiche Technische Hochschule Zürich, Università della Svizzera Italiana Campus, Via Giuseppe Buffi 13, CH-6900 Lugano, Switzerland.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Limongelli
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Bonomi
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Francesco Luigi
authors.initials: FL
authors.lastname: Gervasio
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Michele
authors.initials: M
authors.lastname: Parrinello
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D055592:Biophysical Phenomena; D020134:Catalytic Domain; D051545:Cyclooxygenase 1 / Q000737:chemistry; D051546:Cyclooxygenase 2 / Q000737:chemistry; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008958:Models, Molecular; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry*; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D013816:Thermodynamics
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; C102643:SC 558; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases