Virtual selection of γ-oryzanol derivatives of brown rice (Oryza sativa L.) blocking HMG-CoA reductase in hypercholesterolemia disease

Simvastatin is an inhibitor that has been widely recommended as an anti-cholesterol drug that targets HMG-CoA reductase. Yet, these drugs have limitations due to drug resistance effects. This study aims to select the γ-oryzanol derivatives from brown rice as potential HMG-CoA reductase inhibitors using an in silico approach. Gene ontology and protein interaction of hypercholesterolemia were analyzed using ShinyGO and STRINGdb web server. γ-Oryzanol derivatives were screened using the SwissADME web server to assess their drug-likeness, while the PASS Online web server predicted their bioactivity. γ-oryzanol derivatives were then specifically docked at the site of the binding pocket of HMG-CoA reductase (PDB ID: 1DQ9). The stability interaction of ligan-protein was evaluated using YASARA. Cycloartenyl ferulate is predicted to have more potential anti-hypercholesterolemia bioactivity than other derivatives. γ-Oryzanol derivatives interacted with HMG-CoA reductase through hydrogen bonds in the ferulic component and hydrophobic bonds in the phytosterol component. Cycloartenyl ferulate interacted on key residues Asn658, Phe628, Met655, and Val805 in the NADPH binding domain with the strongest binding affinity (-9.2 Kcal/mol). Cycloartenyl ferulate binds to the NADPH binding domain, similarly to simvastatin, which might prevent the NADPH cofactor from helping enzyme catalyzing. The stability of the cycloartenyl ferulate molecular interaction was close to the simvastatin interaction on HMG-CoA reductase. This study showed that γ-oryzanol derivatives, particularly cycloartenyl ferulate, have strong potential as anti-hypercholesterolemia agents by blocking the NADPH binding domain of HMG-CoA reductase.