Structure-based virtual screening to identify hypocholesterolemic phytochemicals as potent inhibitors of squalene...

Squalene synthase (SQS) plays a crucial role in the cholesterol biosynthetic pathway. Its distinctive strategic position makes it a promising candidate for targeting and developing new anti-hypercholesterolemic agents. To uncover novel phytochemical scaffolds as potential inhibitors of SQS, we employed a structure-based virtual screening approach that involves screening 545 phytochemicals collected from Moroccan aromatic and medicinal plants and filtering them based on RMSD values and their affinity towards the target enzyme. Furthermore, we visualized the interacting amino acid residues to gain insight into the 2D and 3D interactions. The docking process was validated through the re-docking method with the reference co-crystallized complex (PDB id = 3v66, SQS-D3A). The screening resulted in the identification of two phytochemicals, Apigenin 7-O-rutinoside, and Apigenin 7-O-glucuronide, with high affinity for SQS binding sites. Both phytochemicals interact with functionally essential residues of SQS. The drug-likeness and toxicity of the phytochemicals were assessed through ADME-Tox analysis. Later, molecular dynamics simulations were performed by GROMACS software for 100 ns to evaluate the stability and fluctuations of protein-ligand complexes. By examining the trajectories produced by the MD simulations, we monitored complex stability, fluctuation, atomic gyration, H-bond, PCA, and FES. The simulations demonstrated that the interaction between the target and the compounds was stable and consistent. Binding free energy calculations indicated that Apigenin 7-O-rutinoside and Apigenin 7-O-glucuronide exhibited higher binding free energy than the co-crystallized inhibitor (D3A), providing a basis for further research in vitro and in vivo to develop potent SQS inhibitors for the treatment of hypercholesterolemia.