In silico analysis of LDLR isoform gene for the identification of natural inhibitors against familial hypercholesterolemia

Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C), increasing the risk of premature cardiovascular disease. Loss-of-function mutations in the LDL receptor (LDLR) gene are the primary cause, reducing receptor-mediated LDL clearance. Current therapies, including statins, ezetimibe, and PCSK9 inhibitors, aim to enhance LDLR function but may have side effects or limited efficacy, highlighting the need for alternative strategies. This study employed an in silico approach to identify natural phytochemicals capable of modulating LDLR. Five compounds guggulsterone, curcumin, β-sitosterol, oleuropein, and resveratrol were evaluated for binding affinity, pharmacokinetics, and toxicity. LDLR secondary and tertiary structures were predicted using GOR IV, PSIPRED, and AlphaFold, with binding sites identified via DeepSite. Molecular docking using PyRx and CB-Dock2 showed guggulsterone as the top candidate, exhibiting a binding affinity of -9.4 kcal/mol and stable hydrogen bond and hydrophobic interactions with key residues. ADMET analysis indicated high gastrointestinal absorption, Lipinski rule compliance, and minimal organ-specific toxicity, although blood-brain barrier permeability was predicted. These findings suggest that guggulsterone may stabilize LDLR or influence receptor regulation, providing a potential natural therapeutic approach for FH. Further in vitro and in vivo studies are warranted to confirm efficacy and elucidate mechanisms.