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10.1021/ja5112964 http://scihub22266oqcxt.onion/10.1021/ja5112964 C4309031!4309031!25514511     free     free     free Deprecated: Implicit conversion from float 219.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       J+Am+Chem+Soc 2015 ; 137 (1): 70-3 Nephropedia Template TP {{tp|p=25514511|t=2015. Mechanistic Insights into a Classic Wonder Drug?Aspirin |pdf=|usr=}}{{25514511}} gab.com Text Mechanistic Insights into a Classic Wonder Drug Aspirin JO: J Am Chem Soc http://www.kidney.de/pget.php?&tw=1&pmid=25514511 #FOAvip 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. Twit Text FOAVip Mechanistic Insights into a Classic Wonder Drug Aspirin ????J Am Chem Soc http://www.kidney.de/pget.php?&tw=1&pmid=25514511 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=25514511 #FOAvip English Wikipedia <ref>{{Cite pmid|25514511}}</ref> Mechanistic Insights into a Classic Wonder Drug?Aspirin #MMPMID25514511 Lei J; Zhou Y; Xie D; Zhang Y J Am Chem Soc 2015[Jan]; 137 (1): 70-3 PMID25514511show ga 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. äMechanistic Insights into a Classic Wonder Drug?Aspirin (epmc).pdf DeepDyve Pubget Overpricing