Computational studies of Squalene synthase from Panax ginseng: Homology modeling, docking study and virtual screening for a new inhibitor

Through a reductive dimerization of two farnesyl diphosphate (FPP) molecules, Squalene synthase from Panax ginseng (P. ginseng) (PgSS) catalyzes the biosynthesis of squalene, a key cholesterol precutsor, and hence is an attractive site of therapeutic intervention. Thus, the 3D structure of PgSS has been firmly established by homology modeling and was used to relax by MD simulation to get the reliable structure. It is well known that Mg ²⁺ plays an important role in substrate binding. Understanding how PgSS recruits the FPP substrate through Mg ²⁺ is the first and foremost step toward further mechanistic investigations and the design of effective PgSS inhibitors. Quantum mechanical calculation method is used to determine the Mg ²⁺ binding mode. In the first binding motif, the Mg ²⁺ ion is coordinated to D77, D81, and one oxygen atom from the α-and β-phosphates of FPP. In order to determine the important residue of the substrate (FPP) binding, we dock the one FPP to the protein. Arg113 may be an important residue because they form a salt bridge with PgSS. After virtual screening technique of PgSS, a novel natural compound (8002215) has been found with the lowest affinity energy. Then we identify that His266 is the most important anchoring residue for binding with 8002215 because it has strong edge-to-face interaction with inhibitor. Leu205 and Gln206 are important residues for they make hydrogen bonds with inhibitor. Our results may be helpful for further experimental investigations.