Computer-aided design of glucoside brain-targeted molecules based on 4PYP

Abstract Under the guidance of the targeted molecules, brain-targeted liposomes can carry drugs quickly through the blood-brain barrier to achieve the target enrichment of drugs in the brain, so the design of the target molecules is the key to the preparation of high-efficiency brain targeted liposomes. In this study, SYBYL-X2.1.1 software was used to study the number and connection mode of each segment structure (glucose segment, fatty-chain and cholesterol segment) in the design of targeted molecular structure. GROMACS is used for calculation of molecular dynamics simulation, and G_MMPBSA is used for calculation of binding free energy. The results showed that glucose molecules interacted with 4PYP through hydrogen bond and Van der Waals forces. The amount of glucose in the glucoside molecule and the length of the fatty-chain had a significant effect on the interaction between the molecule and 4PYP. On this basis, through a series of optimizations in this study, a glucoside targeted molecule, which had high affinity with 4PYP and stable binding with liposome, was constructed. In summary, the use of computer-assisted screening technology could significantly accelerate the research and development efficiency of new brain-targeted molecules and provide new technical means for the design of new brain-targeted materials.