Molecular Dynamics Simulation Study on the Mechanism of the inhibitory of N,N-dimethyl-3β- hydroxycholenamide (DMHCA) on 3β-hydroxysterol-Δ24-reductase(DHCR24)

Abstract

Abstract 3β-hydroxysterol-Δ24-reductase (DHCR24) is a flavin adenine dinucleotide (FAD)-dependent oxidoreductase. N,N-dimethyl-3β-hydroxycholenamide (DMHCA) is a steroidal ligand of LXRs that exerts anti-atherogenic effects. It is reported that DMHCA also inhibits the enzyme DHCR24 resulting in an accumulation of desmosterol and the reduction of plasma cholesterol, however, the detail mechanism is still unknown. To explore the mechanism of the inhibitory effect of DMHCA on DHCR24, we performed the molecular docking and MD simulations of two complexes of DHCR24-fad-desmosterol and DHCR24-fad-dmhca. We found docking site of the DMHCA to the DHCR24 is very close to that of the desmosterol, the hydrophobic pockets are the same.. The results obtained from MD simulation showed the binding energy of the desmosterol to the DHCR24-fad are − 51.67 kcal/mol while that of DMHCA is -31.48 kcal/mol, suggesting that DMHCA also has a relative high affinity to DHCR24. In addition, the binding of DMHCA to DHCR24 also changed the binding manner of FAD to DHCR24. Taken together, our results for the first time demonstrated at the molecular structure level that DMHCA blocks DHCR24 activity through a competitive-inhibiting manner, which can provide information for the study and design new types of cholesterol-lowering drug by targeting DHCR24.