Computational Investigation of Darapladib and Rilapladib Binding to Platelet Activating Factor Receptor. A Possible Mechanism of Their Involvement in Atherosclerosis

Abstract

Platelet Activating Factor (PAF), the most potent inflammatory mediator, is involved in a wide range of pathophysiological actions. PAF signal transduction is mediated through PAF receptors (PAFR) that are coupled with several isoforms of G-proteins. PAF hydrolysis is mediated through specific enzymes clustered as PAF acetylhydrolases (PAF-AH). The plasma isoform is known as lipoprotein-associated PLA2 (Lp-PLA2), and is considered a marker, or a mediator in the mechanism of atherosclerosis. Darapladib and rilapladib are selective Lp-PLA2 inhibitors. They are, thus, proposed as a novel therapeutic approach for cardiovascular disease (CVD). The data derived from the computational methods used in this paper suggest that darapladib and rilapladib are potential PAFR antagonists, predicted to bind inside the PAF-binding site with a comparable binding affinity to the endogenous agonist (ΔG = -11.1 Kcal mol -1 ). Darapladib (ΔG = -10.6 Kcal mol -1 ) exhibited a higher affinity than rilapladib (ΔG = -8.2 Kcal mol -1 ). The fact that darapladib down-regulates PAFR expression, while PAFR inhibitors down-regulate the expression of CD36, could be the biochemical explanation in the observed necrotic core reduction, both in animals and humans. The reported results in conjunction with bibliographical data lead to the hypothesis that the involvement of darapladib and rilapladib in atherosclerosis could be through direct inhibition of PAF activity as well as modification of PAF metabolism.

Atherogenesis inhibition by darapladib administration in dyslipidemia model Sprague-Dawley rats

“…Darapladib, with its mechanism to inhibit Lp-pLA 2 , can reduce the macrophage uptake of Ox-LDL. [27] This theories correlate with research that state that daily administration of darapladib for 24 weeks can reduce Lyso-PC), that is, the proinflammatory derivation of Ox-LDL, which is created when the oxidative modification of LDL occurs. [26] It indicates that darapladib can lower the activity and level of Ox-LDL.…”

Lowering Inflammation Level by Lp-PLA2 Inhibitor (Darapladib) in Early Atherosclerosis Development: in vivo Rat Type 2 Diabetes Mellitus Model

“…DP administration led to disconnect Lp-PLA2 activity in oxLDL so that the number of macrophages in oxLDL will be also decreased so it can lower inflammation marker level. 26 The effect of DP in this study closely mimic the effect of anti-oxidants such as super oxide dismutase (SOD, anti IL-6 and TNF-α which administered to HFD rat and metabolic syndrome model). HFD administration increased PAT, ROS, unpaired eNOS, cytokine production, macrophage infiltration and leptin.…”