Testing The Universality Of The DOX Method Using The PDBbind Database

Molecular docking software has long been used in the field of drug design with the advantages of high speed and high precision,and has achieved certain results in drug research.However,with the wide application of docking,the research found that the score of the docking software is not very accurate,so there are various problems in the drug design based on all kinds of docking software.In this context,the research group developed a calculation method DOX of high-precision quantum chemistry.The DOX method has been successful uesd in Astex test and in the protein crystal structures with the ligand of HMGR-statins,SDase-inhibitors,3HNRase-inhibitors and NA-inhibitors.To further explore the universality of the DOX method,the DOX2.0 method was tested on a large scale on different protein-ligand complex systems.In this article,we have done the following work:(1)Based on the core set of PDBbind(version 2007),a test set containing 66 protein-ligand complexes covering a wide range of proteins,called 66-test-set,was screened with activity 1 μM as the main criterion.And we test the DOX method on the test set.(2)First,66 complexes were tested on molecular docking method.Molecular docking found a better quality(100-200)conformation space at the MM level.100%of the complexes contained a conformation close to the crystal in the conformation space given by SYBYL(RMSD≤2A).It is the basis for optimization at a higher level of precision.There are still 35%of the systems predicted to have a poor binding conformation(RMSD>2A).(3)The calculation is optimized by the medium precision quantum chemical method PM7 on the conformation space reserved for docking.A reasonable conformation can be found in the top ten binding conformations of the energy ranking,which effectively reduces the number of protein-ligand binding structures and improves the computational efficiency of the DOX method.There are still 18%of the systems predicted to have a poor binding eonformation(RMSD>2A).(4)The high-precision quantum chemical method XO is used to optimize the calculation in the top ten conformation space screened by the PM7 method.In the test results of Surflex@SYBYL,PM7@MOPAC,and XO method,the average RMSD of the predicted conformation is 2-2 A,1.3 A,and 1.2 A,respectively,and the success rate of RMSD<1 A increases sequentially,respectively,to 35%,50%,61%,the percentage of the system with RMSD less than 2A decreases in tum,35%,18%,15%respectively.Through the optimization calculation method with higher precision,the quality of the predicted conformation is greatly improved,which proves DOX a good method.And it also demonstrates the reliability of the DOX method for calculations at higher precision levels.Moreover,the success rate of DOX method on RMSD<2A has reached 85%,the average predicted relative binding energy is 4.64Kcal/mol.It indicates that the DOX method is accurate for most systems of 66 different complex systems and has a certain universality.The binding conformation and binding mode predicted by the DOX method can provide ideas for different types of drug design.The challenging system of the DOX process is the system with hydrophobic group and the system where the ligand is bound to a cavity on the surface of the protein.Through the test analysis,the DOX method can be improved by adding solvation and molecular dynamics,which provides ideas for the development of the DOX method.