Combined computational and pharmacological approach reveals Citrullus colocynthis as a natural PCSK9 inhibitor in insulin resistant rats

This study evaluated the therapeutic effects of Citrullus colocynthis seed extract (CCSE) on PCSK9 expression in a high-fat diet (HFD)-induced insulin resistance (IR) model in Wistar rats. Fifteen phytoconstituents from CCSE were screened for drug-likeness using SwissADME and docked against PCSK9 (PDB ID: 6U26). In vivo, 30 HFD-induced-IR rats were divided into five groups: one control (saline) and four treatment groups received CCSE (100,200,300,400 mg/kg) for 28 days. Hepatic PCSK9 mRNA expression was analyzed by qRT-PCR, with relative fold changes. Data were statistically evaluated by ANOVA. In-silico analysis demonstrated all selected compounds complied with Lipinski’s Rule of Five, indicated favorable oral bioavailability. Topological polar surface area (TPSA: 9.23-55.38 Ų) and number of rotatable bonds (NRB <10) further supported their drug-like properties. Strong binding affinities were of compounds Cyclopropane carboxylic acid and 2,4-di-tert-butylphenol (-7.4 and -5.5 kcal/mol) to PCSK9. In-vivo results showed that CCSE significantly downregulated hepatic PCSK9 mRNA expression at a dose of 300mg & 400mg/kg (p < 0.05 vs. control), with the highest reduction (3.2-fold) observed at the 400 mg/kg dose. CCSE significantly downregulated hepatic PCSK9 mRNA expression and confirmed through both in-silico and In-vivo approaches. This suggests its potential as a natural therapeutic agent for managing metabolic disorders.