Prostaglandins are potent mediators of inflammation and their aberrant synthesis is tied to a number of physiological conditions, including the acute inflammation response and chronic inflammatory diseases such as arthritis and asthma. Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen work by inhibiting prostaglandin production. The target of NSAIDs is cyclooxygenase (COX, also called prostaglandin synthase), which catalyzes the first committed step in the conversion of arachidonic acid to prostaglandins. Two isoforms of COX are known and both forms are inhibited by common NSAIDs: inhibiting COX-2 provides relief from inflammation, pain, and fever, but inhibiting COX-1 can result in dangerous gastrointestinal, pulmonary, and renal damage. This study uses molecular dynamics/thermodynamic integration calculations to develop potent COX inhibitors specific for COX-2 rather than COX-1. Facilities of and software developed in the UCSF Computer Graphics Laboratory are used to visualize calculated structures of protein-ligand complexes. This capability is vital for rationalizing calculated binding free energy differences and proposing new ligands whose structures are complementary to the protein structure.
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