Calculation And Analysis Of Binding Free Energy Of Protein Ligand Alanine Scanning-interaction Entropy For Important Disease Targets

The understanding of the protein-ligand interaction mechanism and the quantitative determination of its binding affinity are very important for drug discovery,design,and development.Although experiments can study the thermodynamic properties of protein-ligand binding,determining binding affinity is time-consuming,laborious,and expensive.However,computational methods for calculating binding affinity have gained more and more attention due to its low cost and fast speed.Recently,our research group have developed the alanine scanning-interaction entropy(ASIE)method,which combines molecular dynamics simulation,MM/GBSA,and interaction entropy methods to quickly and accurately calculate the binding free energy contribution of binding pocket residues and total binding energy in protein-ligand and protein-protein complexes.The first part of this thesis applies the ASIE method to the androgen receptor-ligand interaction system.The androgen receptor is an important therapeutic target for many diseases.This study analyzed the hot residues of androgen receptor-ligand binding systems and calculated the total binding free energy of the complexes.There is a good agreement between the binding free energy calculated by ASIE and the experimental binding data.In terms of correlation coefficient and error analysis,the ASIE method has better results than the traditional MM/GBSA method.In addition,this study used the ASIE method to determine the hot-spot residues in the ligand-binding pocket,and analyzed the interaction mode between the hot-spot residues and the ligand,which is useful for the design of drugs targeting the androgen receptor in the future.In the second part of this thesis,we calculated the binding free energy of seven clinically approved antiandrogens(including the first-and second-generation antiandrogens)and their major metabolites in complex with the wild-type and F876 L mutant androgen receptor,respectively,using the ASIE method.The change of binding free energy contribution of hot-spot residues before and after F876 L mutation was analyzed with the ASIE method,and the molecular mechanism of drug resistance of the F876 L mutant was investigated.In addition,by comparing the total binding free energy calculated by ASIE and MM/GBSA with the experimental values,it was found that the error of the ASIE method was smaller than that of MM/GBSA,and the variation trend of the total binding free energy before and after the mutation was consistent with the experimental results.In the third part of this thesis,the ASIE method was used to quantitatively analyze the free energy contribution of the binding pocket residues in the complex of SARS-Co V-2 main protease and four ligands.The hot-pot residues were identified.Through the ASIE calculation,the energy decomposition of the contributions of the hot-spot and warm-spot residues in the four systems was carried out,and it was found that van der Waals energy accounts for most of the contribution of the hot-spot and warm-spot residues.In addition,the interaction pattern between residue 41HIE(which has the strongest binding free energy contribution in all systems)and small molecules was analyzed.Finally,the sum of each residue's binding free energy contribution is in good agreement with the experimentally values.The results of these calculations should be very helpful in the design and analysis of the SARS-Co V-2 main protease inhibitors.