Molecular Docking and Structure Activity Relationship Studies of NSAIDs. What do they Reveal about IC50?

Background: The cyclooxygenase (COX) enzymes are important biological targets for non-steroidal anti-inflammatory (NSAID) drugs because they can inhibit the prostaglandin synthesis during the inflammatory process. Although COX enzymes are structurally well characterized, accurate ligand docking studies are challenging due to their varied structural and chemical properties. Methods: We conducted molecular docking studies of 30 structurally diverse NSAIDs using two different software packages in an effort to examine if a linear dependency between experimental IC50 values (50% binding inhibition) and binding energies is realistic for this class of compounds. Results: Results showed that the docking technique can approximate the selectivity of NSAIDs via energetic terms but not the IC50. Evaluation of ADME parameters coupled with multiple linear regression was performed to create statistically significant QSAR models correlating IC50 values to physicochemical and biological parameters for the COX-2 enzyme. Conclusion: The distribution of the electrostatic potential, nucleophilicity and electrophilicity was found to be the most important descriptor for drug-enzyme interactions.