Molecular modelling simulations and inhibitory effects of naturally derived flavonoids targeting platelet-activating factor receptor (PAFR)

Background: Platelet-activating factor (PAF) is an agonist mediator in the inflammatory process, which is involved in the interaction with PAF receptor (PAFR) that eventually causes cancers, and respiratory and neurodegenerative diseases. This interaction activates the mitogen-activated protein kinase (MAPK) pathway and leads to a pro-inflammatory cascade. The pathophysiological conditions due to activation of inflammatory cascade could be blocked by PAF antagonists. Objectives: In this study, selected naturally derived flavonoids (flavone, biochanin A, and myricetin) with different functional groups were subjected to molecular modeling and experimental studies to investigate their potential as PAF antagonists. Method: Interactions of flavonoids and PAF were assessed via Autodock Vina for molecular docking and the AMBER program for molecular dynamic simulations. The experimentally antagonistic effects of the flavonoids were also conducted via PAF inhibitory assay to determine the IC50 values. Results: The findings of docking and dynamic simulations have revealed that all selected flavonoids interact with PAFR in the binding site with considerably good binding affinity up to -9.8 kcalmol-1 as compared with cedrol (-8.1 kcalmol-1) as a standard natural PAFR antagonist. The PAFR-flavonoid complexes exhibited four conserved active site residues, which included W73, F97, F174, and L279. The stability of all complexes was attained in a 30 ns simulation. In silico analyses were then compared with the experimental study of PAF inhibitory assay. Inhibitory effects of flavonoids against PAFR showed moderate activities, ranging from 27.8 to 30.8 µgM-1. Conclusion: All studied flavonoids could act as promising PAF antagonists with some enhancement in their structures to exhibit potential antagonistic activity. However, these naturally derived flavonoids demand further investigation at cellular and animal models for the development of new PAF antagonist drug candidates for treating PAF-mediated diseases.