Mechanistic insights into a classic wonder drug-aspirin

Jinping Lei, Yanzi Zhou, Daiqian Xie, Yingkai Zhang

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)70-73
Number of pages4
JournalJournal of the American Chemical Society
Volume137
Issue number1
DOIs
StatePublished - Jan 14 2015

Fingerprint

Aspirin
Enzyme inhibition
Acetylation
Pharmaceutical Preparations
Molecular dynamics
Enzymes
Sampling
Kinetics
Cyclooxygenase 2
Computer simulation
Substrates
Molecular Dynamics Simulation
Prostaglandin-Endoperoxide Synthases
Protein Isoforms
Anti-Inflammatory Agents
Pharmacology
Neoplasms

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Mechanistic insights into a classic wonder drug-aspirin. / Lei, Jinping; Zhou, Yanzi; Xie, Daiqian; Zhang, Yingkai.

In: Journal of the American Chemical Society, Vol. 137, No. 1, 14.01.2015, p. 70-73.

Research output: Contribution to journalArticle

Lei, Jinping ; Zhou, Yanzi ; Xie, Daiqian ; Zhang, Yingkai. / Mechanistic insights into a classic wonder drug-aspirin. In: Journal of the American Chemical Society. 2015 ; Vol. 137, No. 1. pp. 70-73.
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