7-O-methylpunctatin is a potential inhibitor of human arachidonate 5-lipoxygenase: molecular and structural insights into anti-atherosclerosis therapeutics.

We have recently demonstrated that 7-O-methylpunctatin (MP), a novel homoisoflavonoid, suppresses inflammation-induced arterial pathogenesis. However, the precise biochemical mechanisms underlying its atheroprotective effects remain elusive. In this study, we employed various in silico studies to elucidate MP's plausible potential and the specific molecular pathways through which it exerts its influence on atherosclerosis. Our analysis of MP's pharmacokinetic, physicochemical, and toxicological properties revealed a profile characterized by favorable absorption, efficient metabolism and excretion, and minimal toxicity. Through target identification and protein-protein interaction analyses, we identified ALOX5 as a pivotal hub gene-an enzyme critically involved in the pathogenesis of atherosclerosis. Furthermore, we identified ten transcription factors and four kinases as potential targets. Molecular mechanics/generalized-born surface area calculations, complemented by time-scale molecular dynamics simulations, revealed that MP binds to ALOX5 with high affinity, modulating its structural stability, rigidity, compactness, overall folding pattern, and residual correlations and motions. These findings corroborate previous in vitro and in vivo investigations that underscore the anti-atherosclerotic effects of ALOX5 inhibition, thereby positioning MP as a promising therapeutic candidate for combating atherosclerosis.