Computational screening of the potent bioactive compound of brown rice (Oryza sativa L.) against obesity-related hypercholesterolemia by targeting FASN, HMGCS1, and HMGCR

Obesity-related hypercholesterolemia, a significant risk factor for cardiovascular disease, is metabolic disorder characterized by elevated fatty acid and cholesterol biosynthesis. Brown rice (Oryza sativa L.), a functional food with diverse pharmacological properties, is believed to possess potent anti-obesity and anti-cholesterol effects. This study aimed to identify a potent compound from brown rice that could inhibit key enzymes involved in lipid biosynthesis: fatty acid synthase (FASN), 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1), and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). To achieve this, bioactive compounds from brown rice were screened for drug-likeness, toxicity, and bioactivity. Molecular docking was performed to evaluate the binding affinities of selected compounds to the target proteins and was continued molecular dynamic simulation. Among the twenty-six compounds analyzed, five were identified as promising candidates for anti-obesity and anti-cholesterol activities. Trans-3-hydroxycinnamic acid emerged as the most potent compound, exhibiting strong binding affinities to the active sites of FASN (Leu2222, Phe2423), HMGCS1 (Cys129, Tyr171, Ser377), and HMGCR (Glu559, Gly806, Thr809, Met655). Importantly, this compound formed stronger and closer interactions with FASN (-7.4 kcal/mol) and HMGCS1 (-7.2 kcal/mol) compared to the respective drug controls (orlistat and hymeglusin). However, its binding affinity to HMGCR (-6.2 kcal/mol) was weaker than that of simvastatin (-8.3 kcal/mol). Notably, molecular dynamic results demonstrated that the interaction trans-3-hydroxycinnamic acid with FASN and HMGCR was stable. By effectively inhibiting FASN and HMGCR1, trans-3-hydroxycinnamic acid from brown rice has the potential to regulate lipid metabolism, suppress obesity, and prevent complications associated with hypercholesterolemia.