Molecular basis of cyclooxygenase enzymes (COXs) selective inhibition.
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.
Limongelli
Vittorio
V
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.
Bonomi
Massimiliano
M
Marinelli
Luciana
L
Gervasio
Francesco Luigi
FL
Cavalli
Andrea
A
Novellino
Ettore
E
Parrinello
Michele
M
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
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