Accurate Prediction Of Binding Modes Of Multirotate Bond Inhibitors

Accurately obtaining the three-dimensional structure of the protein-ligand interaction is one of the most important issues in the field of structure-based drug design.It is usually obtained by experimental methods and theoretical methods.However there are still many limitations on getting accurate structure information of biological macromolecules such as proteins and drug complexes by experimental means.Using modern molecular simulation technology to theoretically calculate the interaction between biomacromolecules and ligand drugs is an important supplement to experimental methods.Within which,the molecular docking is one of the most commonly used techniques in receptor-based drug design(RBDD),which can rapidly predict the binding mode of a ligand in a protein receptor binding site and the strength of binding.Limited by its calculation principle,however,there are still some deficiencies ahead for the accuracy of predicting.Based on the above theoretical background,our group developed a new high-precision calculation method DOX.This method is based on the Conformation Search Across Multiple-level Potential-energy-surface(CSAMP)strategy,optimizing is achieved from the rough level of macromolecular docking which on the basis of molecular force field to the intermediate level of semi-empirical quantum mechanics PM7,and finally the fine horizontally extended ONIOM(XO)calculation is realized.Owing to this process,the candidate constellations of the conformation spaces are minimized from hundred to ten,and finally a top candidate binding constellation is predicted.In order to systematically investigate the accuracy and practicability of the DOX method and show its improvement on traditional molecular docking technology,at first we constructed 38 highly active protein-inhibitor complexes a of human immunodeficiency virus type 1(HIV-1)to form a test system.The outstanding features of this test set are:(1)the protein-inhibitor binding conformation has many rotatable bonds;(2)the number of the inhibitor molecular is very large,up to 600;(3)the binding mode of the inhibitor molecule to the receptor protein is complex,and the hydrophobic interactions are numerous.Through the large number of systematically tests,the average value of RMSD between the predicted conformational geometry obtained by the DOX method and the inhibitor molecules in the crystal structure is 0.67 A,and the average relative binding energy was 3.87 Kcal/mol.The test results convincingly demonstrate the advantages of the DOX approach.Then,10 different protein inhibitor complexes of the "core set" in the PDBBind2007 database were used to further test the performance of the DOX method.The inhibitor molecules of this test set have similar characteristics to the HIV-1 system.The average value of RMSD between the predicted conformational geometry obtained by the DOX method and the inhibitor molecules in the crystal structure is 2.24 A,and the average relative binding energy was 4.95 Kcal/mol.The test results show that the DOX method based on SCAMP strategy can accurately predict the binding mode of multi-rotation bond inhibitors.These also indicate it has flaws,which will be the foundation of future improvement.