Molecules · 8 authors, 2 centres
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This study identified four potential inhibitors of DHCR24, the enzyme catalyzing the final step of cholesterol synthesis, through virtual screening. Irbesartan, an existing antihypertensive drug, showed the most potent cholesterol-lowering effect in cell and mouse models, with an IC50 of 602 nM against DHCR24. These findings suggest that repurposing irbesartan could benefit patients with both hypertension and hyperlipidemia.
**Background:** Hyperlipidemia is a major risk factor for cardiovascular diseases and cancer. Current cholesterol-lowering drugs, such as statins, have side effects and may disrupt important intermediate metabolites. DHCR24 catalyzes the final step of cholesterol biosynthesis, converting desmosterol to cholesterol. Inhibiting DHCR24 could lower cholesterol while allowing accumulation of desmosterol, which may have anti-inflammatory effects. This study aimed to identify novel DHCR24 inhibitors through virtual screening and evaluate their cholesterol-lowering effects.
**Methods:** The 3D structure of DHCR24 (amino acids 23–516) was predicted using I-TASSER and optimized with NAMD2.9. The DrugBank database was screened using AutoDock Vina and AutoDock 4.2 to identify compounds binding to the desmosterol-binding pocket. Four candidates (irbesartan, risperidone, tolvaptan, conivaptan) were selected based on binding energy and drug-likeness. Molecular dynamics simulations (30 ns) and MM-GBSA binding free energy calculations were performed. In vitro, HepG2 cells were treated with candidates, and intracellular cholesterol was measured by filipin staining and HPLC. In vivo, C57BL/6J mice were fed a high-fat diet for 4 weeks with or without drug treatment (risperidone 0.7 mg/kg, tolvaptan 1 mg/kg, irbesartan 6 mg/kg, conivaptan 1 mg/kg, simvastatin 20 mg/kg). Serum lipids (TC, TG, LDL-C, HDL-C) were measured, and liver histology was assessed by H&E staining. LDL-R expression was analyzed by Western blot. DHCR24 enzyme activity was measured using an immune complex activity assay with HPLC detection, and IC50 for irbesartan was determined.
**Key Results:** Virtual screening identified four candidates with low binding energy. Molecular dynamics showed irbesartan bound to the same pocket as desmosterol, forming two hydrogen bonds with Leu252 and Hid377, suggesting competitive inhibition. In HepG2 cells, all four drugs significantly reduced cholesterol content compared to controls (p < 0.001). In mice, irbesartan significantly lowered serum TC, TG, and LDL-C while increasing HDL-C compared to the high-fat diet control. Liver histology showed reduced lipid vacuolation in all drug groups. Western blot revealed that irbesartan upregulated LDL-R expression similarly to simvastatin. The DHCR24 enzyme activity assay confirmed that irbesartan inhibited DHCR24 with an IC50 of 602 nM.
**Clinical Implications:** This study demonstrates that irbesartan, an FDA-approved drug for hypertension and type 2 diabetes, effectively lowers cholesterol by inhibiting DHCR24. It may be particularly suitable for patients with both hypertension and hyperlipidemia. The findings support drug repurposing and suggest that targeting DHCR24 is a viable strategy for developing new cholesterol-lowering therapies. However, further studies are needed to clarify the exact mechanism and evaluate long-term safety.