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As the most frequent cause of death in the world today, cardiovascular and cerebrovascular diseases are often a consequence of an arteriosclerotic process with a complex background. Atherosclerosis is a diffuse process that starts early in childhood and progresses asymptomatically through adult life. Later in life, it is clinically manifested as coronary artery disease, stroke, transient ischemic attack, and peripheral arterial disease. Approaches that retard or even reverse atherosclerotic lesion development in humans for prevention of plaque disruption and acute coronary events include better control of risk factors, such as reducing the plasma cholesterol levels. Nevertheless, even when the atherosclerotic plaque disruption cannot be prevented, a beneficial effect of antiplatelet and anticoagulant agents has been observed in the prevention of acute coronary events. Currently, the most widely used antiplatelet agents are aspirin, dipyridamole, glycoprotein IIb/IIIa antagonists, and thienopyridines. However, these drugs also have several limitations. For example, in patients with vascular disease aspirin was less efficacious than clopidogrel. For the latter, despite its effectiveness, clopidogrel negatively affects its clinical efficacy. The active metabolite of clopidogrel irreversibly and selectively inhibits the adenosine diphosphate (ADP) receptor. Once the receptor is activated, the drug will irreversibly bind to platelets. Consequently, clopidogrel has a slow onset and slow offset of pharmacological action. For example, in some acute settings, such as suffering from bleeding or a trauma and requiring emergency surgery, it is difficult for clopidogrel to deal with. In addition, for those people who are resistant to the effects of clopidogrel, this drug will be also less helpful. Therefore, intensive efforts have been devoted toward the discovery of innovative antiplatelet agents that are more potent and safe, direct acting, and orally bioavailable, which would be paramount to meeting the demands of the urgently needed therapeutic weapons against the ADP receptor. ADP is an important platelet agonist, where even minute concentrations can induce rigid platelet aggregate formation. Its crucial roles in modulating the thrombosis and hemostasis were rapidly recognized, but the molecular identity of its receptors remained for a long time elusive. P2Y1 and P2Y12, as two important P2Y receptors, moderate the effect of ADP on platelets. The Gq-coupled P2Y1 receptor 9 is responsible for a transient rise in Ca, while the Gi-coupled P2Y12 receptor 10 refers to the inhibition of adenylate cyclase, and both of them are implicated in the transduction of the ADP signal. For normal platelet aggregation, it requires simultaneous activation of the Gq and Gi pathways by ADP. Among them, activation of the Gq pathway through P2Y12 causes the changes of the platelet shape and a

journal of chemical information and modeling

Combined 3D-QSAR, Molecular Docking, and Molecular Dynamics Study on Piperazinyl-Glutamate-Pyridines/Pyrimidines as Potent P2Y<sub>12</sub> Antagonists for Inhibition of Platelet Aggregation

Combined 3D-QSAR, Molecular Docking, and Molecular Dynamics Study on Piperazinyl-Glutamate-Pyridines/Pyrimidines as Potent P2Y12 Antagonists for Inhibition of Platelet Aggregation

Combined 3D-QSAR, Molecular Docking, and Molecular Dynamics Study on Piperazinyl-Glutamate-Pyridines/Pyrimidines as Potent P2Y₁₂ Antagonists for Inhibition of Platelet Aggregation