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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.

SUBMITTER: Limongelli V 

PROVIDER: S-EPMC2851773 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Molecular basis of cyclooxygenase enzymes (COXs) selective inhibition.

Limongelli Vittorio V   Bonomi Massimiliano M   Marinelli Luciana L   Gervasio Francesco Luigi FL   Cavalli Andrea A   Novellino Ettore E   Parrinello Michele M  

Proceedings of the National Academy of Sciences of the United States of America 20100309 12


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-5  ...[more]

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