3D-QSAR,molecular Docking,and Molecular Dynamics Studies Of Indazole As Inhibitors Of PI3Kδ Kinase

Objective:Chronic obstructive pulmonary disease（COPD）has become a major global public health problem that threatens human health.It has been reported that PI3Kδsignaling pathway involves in the pathophysiological process of COPD.Therefore,PI3Kδhas attracted more and more attention as a potential new target for the treatment of COPD.At present,a series of highly active and highly selective indazole PI3Kδkinase inhibitors have been reported in the literature.However,the relationship between the structure and activity of this class of compounds and the interaction pattern between the compound and PI3Kδkinase are not yet clear.In this study,a series of PI3Kδkinase inhibitors with a indazole skeleton were used for 3D-QSAR,molecular docking,and molecular dynamics simulation studies,elucidating the mechanism of action between indazole compounds and PI3Kδkinase and obtaining key information between their activity and structure.We hope to provide a reliable theoretical basis for the further design and optimization of PI3Kδkinase inhibitors.Method:In this study,molecular docking and molecular dynamics simulation were used to study the mechanism of the action of indazole and PI3Kδkinase.Based on other experimental studies,a three-dimensional quantitative structure-activity relationship（3D-QSAR）method was used to build Co MFA and Co MSIA models to obtain the relationship between the structure and activity of inhibitor compounds.Finally,we designed 26 PI3Kδkinase inhibitors on this basis,and predicted their activity and ADMET.Results:All of 47 compounds can be docked into the binding pocket of the PI3Kδkinase by the key residues Val828,Ser831,Phe751,Thr750,Trp760,Met900,Ile910,Lys779,Asp 753,Ile777,Asp911 and Tyr813,and the indazole ring of all the compounds can form a stable hydrogen bond with the residue Val828.Comparing the binding modes of compound 47 and 05,it was found that the conformation of the two compounds in the PI3Kδkinase binding site was quite different,compound 47 is more stable with PI3Kδkinase.The RMSD trajectories of the 47-5UBT and 05-5UBT systems show that after 20 ns,the two complex systems tend to balance slowly.The residues located at the active site have low RMSF values,but the comparison of the high active molecular system（47-5UBT）with the low active molecular system（05-5UBT）and the key residue Asp753,Asp911,Lys779,Tyr813,Ser831,Ile777,Met900,Ile910,Trp760,Ile825 and Ser754 in 47-5UBT system showed a lower RMSF value.In the process of molecular dynamics simulation,compound 47 and PI3Kδkinase formed a number of hydrogen bond interactions.Co MFA and Co MSIA models were constructed by 3D-QSAR method.In the Co MFA model,q²=0.719,r²=0.972,r²_bs=0.982,r²_pred=0.739,in the Co MSIA model,q²=0.649,r²=0.983,r²_pred=0.604,r²_bs=0.986.Through the three-dimensional equipotential map,the effects of different field effects on the biological activity of these carbazole compounds were obtained.The designed 26 PI3Kδcompounds have high predictive activity and can be docked into the binding pocket of PI3Kδkinase.In addition,the predicted ADMET data showed that most of the designed compounds have higher absorption,distribution and lower clearance rate.Conclusion:PI3Kδhas attracted intense attention as a new target for the treatment of COPD.In this study,a series of carbazole derivatives were subjected to 3D-QSAR,molecular docking and molecular dynamics simulations.Through molecular docking and molecular dynamics simulation studies,we have a certain understanding of the binding mechanism of carbazole compounds with PI3Kδkinase.The Co MFA and Co MSIA models constructed by the 3D-QSAR method will help to better understand the relationship between the structure and activity of indazole compounds and determine the structural characteristics that affect the activity of the compounds.On this basis,26 compounds were designed,and their activity and ADMET properties were predicted.We hope to provide a theoretical basis for the further synthesis of efficient PI3Kδinhibitors.This thesis comprises the following sections:1.It starts with a brief overview of the PI3K kinase family,including structural classification and function,signaling pathways and and the relationship with chronic obstructive pulmonary disease,and then it was briefly described the research progress of PI3K kinase.2.It was briefly introduced the development and basic principles of computer-aided drug design methods used in this article,including quantitative structure-activity relationship（QSAR）,molecular docking,and molecular dynamics methods.3.Molecular docking and molecular dynamics simulations of a series of indazole PI3Kδkinase inhibitors were conducted to elucidate the mechanism of action between indazole compounds and PI3Kδkinase.Next,the molecular dynamics simulation method was used to study the details of the combined process indazole inhibitors with PI3Kδkinase.This further validates the reliability of the docking result.4.A 3D-QSAR study was performed on a series of highly selective indazole PI3Kδinhibitors to establish stable and reliable comparative molecular field analysis（Co MFA）and comparative molecular index analysis（Co MSIA）models.The relationship between the structure and activity of the compound was analyzed according to the obtained model.5.Based on three-dimensional equipotential map and docking patterns,26 PI3Kδinhibitors were designed,and their activity value and ADMET were predicted.In order to demonstrate their binding affinity to P13Kδ,these compounds were subjected to a molecular docking study.Finally,a summary and prospect for this research work was performed as a conclusion.