(14) As shown in Figure 1, our simulation results indicate that the binding mode of aspirin is very similar between two COX enzymes: aspirin is stabilized in the active site by forming hydrogen bonds with hydroxyl groups of Tyr385 and Ser530, and the carboxyl group of aspirin is open to bulk waters and forms three additional hydrogen bonds with water molecules on average. Here we first docked aspirin into the active site of crystal structure of COX-1 and COX-2 (PDB codes 1Q4G and 3NT1, respectively (10, 11)) using Autodock 4.2, (12) and carried out extensive explicit water classical molecular dynamics (MD) simulations with the amber99SB force field (13) and the Amber11 molecular dynamic package. ![]() Thus, our first essential task is to computationally characterize this important intermediate for both COX enzymes. Unfortunately, due to its transient nature, no structure of the COX-aspirin non-covalent complex has been determined in spite of extensive structural work on COX enzymes. The time-dependent and irreversible inhibition of COX by aspirin is generally believed to occur in two steps, in which a rapid reversible non-covalent binding is followed by an irreversible first-order reaction, (7a) i.e., where is the non-covalent binding complex of COX and aspirin, a key intermediate in this irreversible inhibition process. To fill this gap, here we have employed state-of-the-art computational approaches to systematically investigate aspirin covalent inhibition of both COX isoforms. (7) In spite of significant efforts being devoted to develop aspirin-like molecules in order to improve its COX-2 selectivity (8) or reduce the gastrotoxicity, (9) there has been little understanding regarding how this difference in aspirin inhibition potency against the two COX isoforms is achieved. (4) In light of COX-1’s role in gastric protection (5) and COX-2’s role in inflammation, (2a, 6) lack of COX-2 selectivity has generally been considered as a main drawback of aspirin, which accounts for aspirin’s main side effects, such as the gastric ulceration. (3) Actually, aspirin can covalently inhibit both major isoforms of COX and is 10–100 times more potent against COX-1 than against COX-2. (2) However, the biochemical mechanism of aspirin’s therapeutic action is unique: aspirin covalently modifies the COX-2 enzyme through acetylation of Ser530 near its active site, which prevents proper binding of the native substrate and thus leads to its irreversible inhibition. Like many other nonsteroidal anti-inflammatory drugs (NSAIDs), the primary principal pharmacological molecular target for aspirin is cyclooxygenase-2 (COX-2). ![]() (1) Besides its wide use in the treatment of inflammation, fever, and pain for over a century and its well-known benefit in the prevention/treatment of cardiovascular diseases, (1f, 1g) regular aspirin intake has recently been convincingly shown to reduce the overall risk of certain cancers. The structural origin of this differential inhibition of the COX enzymes by aspirin has also been elucidated.Īspirin (acetylsalicylic acid, or ASA), an ancient anti-inflammatory agent, is a classic wonder drug. 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. 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. 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. 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. Aspirin, one of the oldest and most common anti-inflammatory agents, has recently been shown to reduce cancer risks.
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