Bioinformatics Examination of Quercetin from Salacca zalacca Skin, Fruit, and Seed as a Potent Active Compounds Against Hypercholesterolemia Via PCSK9 Inhibition

Abstract

          Hypercholesterolemia is a high-risk factor for cardiovascular disease. The increasing prevalence of hypercholesterolemia necessitates effective therapy. One of the novel targets is proprotein convertase subtilisin/kexin type 9 (PCSK9). However, the high cost of PCSK9 inhibitors limits their availability in low-income and middle-income countries. Salacca zalacca (SZ) is an herbal plant with various pharmacological properties, especially cholesterol metabolism. Novel PCSK9 inhibitors from herbal plants may be promising for drug development based on bioinformatic predictive analysis. This study identified SZ compounds as antihypercholesterolemic agents targeting PCSK9 inhibitors and their mechanisms. Pharmacokinetic properties and biological activities were analyzed using the pkCSM and Way2 drug PASS online databases. Molecular docking was performed using PyRx v9.0, PyMOL, and molecular dynamics using the YASARA software. 4-{[(1R)-6-methoxy-1-methyl-1-{2-oxo-2-[(13-thiazol-2-yl)amino]ethyl}-1,2,3,4 tetrahydroiso-quinolin-7-yl]oxy}benzoic acid (PV7) was used as the control. 25 compounds were identified in SZ, and 8 compounds showed good oral bioavailability. Molecular docking showed that quercetin had the strongest binding affinity for PCSK9 (8.167 ± 0.153 kcal/mol). It was not significantly stronger than the control (8.067 ± 0.153 kcal/mol) and bound to the same binding residues (TRP 461, ASP 360, SER 462, ARG 357, ARG 458, VAL 333, THR 335, PRO 331, and CYS 358). In addition, molecular dynamic simulation showed a stable interaction between quercetin and PCSK9 with an average RMSD of 3.5 Å. Therefore, quercetin, a phytochemical compound from SZ, is a promising candidate for anti-hypercholesterolemia by targeting PCSK9 inhibitors.

HIGHLIGHTS

• PCSK9 inhibitors are considered novel agents and effective treatments for hypercholesterolemia.
• PCSK9 contained several critical residues at ASP360, ARG357, ARG458, and ARG476.
• Salacca zalacca compounds show promising anticholesterol properties through PCSK9 inhibition.
• Quercetin has the highest binding affinity among the SZ compounds and interacts stably with the PCSK9 protein.

GRAPHICAL ABSTRACT