title: Mechanistic insights into a classic wonder drug--aspirin.
abstract: Aspirin, one of the oldest and most common anti-inflammatory agents, has recently been shown to reduce cancer risks. The principal pharmacological effects of aspirin are known to arise from its covalent modification of cyclooxygenase-2 (COX-2) through acetylation of Ser530, but the detailed mechanism of its biochemical action and specificity remains to be elucidated. In this work, we have filled this gap by employing a state-of-the-art computational approach, Born-Oppenheimer molecular dynamics simulations with ab initio quantum mechanical/molecular mechanical potential and umbrella sampling. Our studies have characterized a substrate-assisted inhibition mechanism for aspirin acetylating COX: it proceeds in two successive stages with a metastable tetrahedral intermediate, in which the carboxyl group of aspirin serves as the general base. The computational results confirmed that aspirin would be 10-100 times more potent against COX-1 than against COX-2, and revealed that this inhibition specificity between the two COX isoforms can be attributed mainly to the difference in kinetics rate of the covalent inhibition reaction, not the aspirin-binding step. The structural origin of this differential inhibition of the COX enzymes by aspirin has also been elucidated.
authors.affiliation: Institute of Theoretical and Computational Chemistry, Laboratory of Mesoscopic Chemistry, School of Chemistry and Chemical Engineering, Nanjing University , Nanjing 210093, China.
authors.forename: Jinping
authors.initials: J
authors.lastname: Lei
authors.forename: Yanzi
authors.initials: Y
authors.lastname: Zhou
authors.forename: Daiqian
authors.initials: D
authors.lastname: Xie
authors.forename: Yingkai
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000107:Acetylation / Q000187:drug effects; D001241:Aspirin / Q000737:chemistry / Q000494:pharmacology*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011789:Quantum Theory; D013329:Structure-Activity Relationship
chemical_list: D016861:Cyclooxygenase Inhibitors; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D001241:Aspirin