Mechanism of action in a 4,5-diarylpyrrole series of selective cyclo-oxygenase-2 inhibitors.
Using semi-empirical AM1 calculation and 6.31G* basis sets, we have calculated the energy of the highest-occupied molecular orbital (E(HOMO)) for anti-inflammatory 4,5-diarylpyrroles which have been shown to have inhibitory activity on cyclooxygenase COX-2, an inducible enzyme expressed during inflammation. We have found a correlation between the E(HOMO) of a molecule and its COX-2 inhibition. However, no correlation was observed between E(HOMO) and the inhibition efficiency of cyclooxygenase-1 (COX-1), the constitutively expressed enzyme, protective to the organism. This result suggests that the inhibitions of the two isoforms follow different molecular mechanisms.
Laboratoire de Chimie Organique Physique, Université des Sciences et Technologies de Lille, Villeneuve d'Ascq, France.
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D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010084:Oxidation-Reduction; D011451:Prostaglandin-Endoperoxide Synthases / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D011758:Pyrroles; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases