Unraveling the Potential of Hypericin: A Novel Approach to Targeting PCSK9 Mutations in Cholesterol Management

Abstract

AbstractProprotein convertase subtilisin/kexin type 9 (PCSK9) plays a pivotal role in regulating cholesterol metabolism by promoting the degradation of low-density lipoprotein receptors (LDLR), leading to elevated levels of LDL cholesterol in the bloodstream. Recent studies have identified key residues--Arg-194, Asp-374, and Phe-379--that are crucial for the interaction between PCSK9 and LDLR, and mutations in these residues can significantly alter this interaction. In this study, we employed molecular docking and in silico mutational analysis to assess the binding affinities of natural compounds, including Hypericin, amentoflavone, Bilobetin, Gingetin, and Progesterone, to wild-type and mutant PCSK9. We explored nine specific PCSK9 mutations (R194, D374Y, F379), targeting changes in residues known to influence LDLR binding affinity. Our results indicate that Hypericin demonstrates favorable binding to wild-type PCSK9, interacting with the critical residues involved in LDLR binding, while other mutations yield diverse effects on compound affinities. Notably, certain mutations, such as R194A and D374Y, significantly impact binding affinities, revealing both potential benefits and challenges in targeting PCSK9 with natural compounds. This study provides insights into potential therapeutic strategies for modulating PCSK9 activity and suggests new avenues for developing safer, more effective treatments for hypercholesterolemia.