Molecular Docking Based On Small Molecule Polarization And Structure-based Drug Design

Molecular docking is mainly used to evaluate the binding mode and the interaction energy between two or more molecules.Semi-flexible docking is generally used to analyze the binding energy between the target and the small molecule ligand.In the docking process,the conformation of the receptor is fixed,and the conformation of the small molecule ligand is allowed to vary over a certain range.This method ensures the accuracy of the molecular docking as well as the computational efficiency.The traditional molecular docking method to evaluate the protein-ligand electrostatic interaction is mainly based on non-polarized force fields.However,it has been found that it is difficult to accurately describe the electrostatic interactions if the system has many electrostatic interactions,and the describe are often unreliable or even wrong.Therefore,based on the polar groups in the compounds,the polarizable bond model of small molecules was developed and applied to molecular docking in this work.First,polar groups were summarized from various compound databases and classified into 13 kinds.Secondly,an appropriate molecular model（for each kind of polar groups）was constructed,and sufficient molecular conformation was obtained by molecular simulation.For each conformation,quantum chemical calculations were carried out in the gas phase and the liquid phase respectively.Then,the polarizable bond parameters of the polar bonds were obtained and applied to the molecular docking.In the molecular docking process,the molecular docking（OPLS₂005 Dock）of 38 protein-ligands was carried out based on the Glide SP method.And on the basis of OPLS₂005 Dock,the EPB（Effective Polarizable Bond）charge of the small molecule was recalculated according to the environmental residues within 5? around the ligand,and then the EPB charge was used in the following docking process（EPB Dock）.The results showed that EPB Dock could represent the crystal structure better,which indicated the reliability of the small molecular EPB charge and the importance of small molecular polarization in molecular docking.Further research on 80 protein-ligand complex structures were tested by using OPLS₂005 Dock,EPB Dock and iterative molecular docking（Optimized Docking）based on the small molecular EPB charge.The statistical results showed that for most systems,the molecular docking based on the small molecular EPB charge could effectively improve the accuracy of molecular docking.Compared with EPB Dock,Optimized Docking can further improve the accuracy of the molecular docking with similar computing time.With the development of structural crystallography and computational methods,more and more three-dimensional structures of disease-related proteins have been determined,of which structure-based drug design has attracted growing attention.In structure-based drug design,how to construct small molecular databases for screening and how to carry out molecular optimization has always been an important issue.Thus,building a specific small molecular database for specific targets based on the proteinligand interactions and the physical-chemical properties of the binding site can improve the screening efficiency as well as the hit rate.After the activity had been determined,molecular optimization was carried out by means of fragment replacement or fragment growth according to the activity data and the structural information of the binding site.Compared with traditional drug discovery,structure-based drug design may not provide definite results.However,it can provide additional information to reduce the cost of experimental screening and hasten the process of drug development.In the CDK2 protein system,nearly 2,000 molecules were designed via fragment growth,and three of the nine compounds screened had a higher affinity（score）than the inhibitor H717.In the PptT protein system,the skeleton transition was carried out via fragment replacement,with the designed molecule retaining the interactions between the original ligand and the target protein.The results proved that molecular optimization plays an important role in structure-based drug design.