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Structure-based QSAR study on differential inhibition of human prostaglandin endoperoxide H synthase-2 (COX-2) by nonsteroidal anti-inflammatory drugs

Posted June 8th, 2010 by pschmidtke
TitleStructure-based QSAR study on differential inhibition of human prostaglandin endoperoxide H synthase-2 (COX-2) by nonsteroidal anti-inflammatory drugs
Publication TypeJournal Article
Year of Publication2002
AuthorsPouplana, R, Lozano JJ, Perez C, Ruiz J
JournalJournal of computer-aided molecular design
Volume16
Issue10
Pagination683 - 709
Date Published2002/10//
KeywordsAmino Acids/chemistry; Anti-Inflammatory Agents, Competitive; Computer Simulation; Crystallography/methods; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors/chemistry; Electrochemistry/methods; Energy Transfer; Enzyme Activation; Humans; Isoenzymes/antagonists & inhibitors/chemis, Molecular; Molecular Conformation; Motion; Prostaglandin-Endoperoxide Synthases/chemistry; Protein Binding; Protein Conformation; Structure-Activity Relationship; Substrate Specificity; Water/chemistry, Non-Steroidal/chemistry; Binding Sites; Binding
AbstractThe prostaglandin-endoperoxide H synthase-1 (PGHS- 1) and prostaglandin-endoperoxide H synthase-2 (PGHS-2) are the targets of nonsteroidal anti-inflammatory drugs (NSAIDs). It appears that the high degree of selectivity for inhibition of PGHS-2 shown by certain compounds is the result of two mechanisms (time-dependent, time-independent inhibition), by which they interact with each isoform. Molecular models of the complexes formed by indomethacin, sulindac, fenamates, 2-phenylpropionic acids and selective cyclooxygenase-2 (COX-2) inhibitors with the cyclooxygenase active site of human PGHS-2 have been built, paying particular attention to water molecules that participate in the hydrogen-bonding network at the polar active site entrance. The stability of the complexes has been assessed by molecular dynamics simulations and interaction energy decomposition analysis, and their biological significance has been discussed in light of available X-ray crystallographic and kinetic results. The selective PGHS-2 inhibitors exploit the extra space of a side-pocket in the active site of PGHS-2 that is not found in PGHS-1. The results suggest that active site hydration together with residues Tyr355, Glu524, Arg120 and Arg513 are crucial to understand the time-dependent inhibition mechanism. A marked relationship between the isoform selectivity and tightly interactions with residues into the side pocket bordered by Val523 is also found.