3D-QSAR, Docking And Molecular Dynamics Simulations Studies On P2Y₁ And P2Y₁₂ Receptor Inhibitors

P2Y₁ and P2Y₁₂ receptors are two important G protein coupled receptors in human body,which are mainly distributed in platelets and play a key role in the process of blood coagulation.In the process of platelets coagulation result from vascular damage,P2Y₁ and P2Y₁₂ receptor are activated by two adenosine monophosphate?ADP?,and a series of coupling reaction are occurred,then increasing the concentration of Ca2+ in platelets.Finally,the fibrin glued and caused platelet aggregation.Therefore,inhibiting P2Y₁ and P2Y₁₂ receptors can effectively prevent platelet aggregation,and it is of great significance in the prevention and treatment of thrombotic diseases.The clinical application of P2Y₁₂ receptor have been more and more widely in thrombosis,since the list of P2Y₁₂ inhibitor of ticlopidine,including thienopyridine and later.But All of them have some common side effects and are weak in long-term treatment.So,the design of new antithrombotic drugs by inhibiting P2Y₁ and P2Y₁₂ receptors are very urgent.Fortunately,some new molecules show good platelets inhibition ability in vitro,but the structure-activity relationship and receptor inhibition mechanism are not clear and the other related theoretical studies in this field are very little.Therefore,exploring the mechanism of the inhibitors and receptor with quantitative structure-activity relationship?QSAR?,molecular docking and molecular dynamics simulation are important to design new P2Y₁ or P2Y₁₂ receptor inhibitors.We selects two groups of P2Y₁₂ receptor inhibitors and a group of P2Y₁ receptor inhibitors to do some theoretical researchs in the methods of three-dimensional quantitative structure-activity relationship?3D-QSAR?,molecular docking and molecular dynamics simulation in this paper.This study established the 3D-QSAR models with significant effective and good prediction ability,and summarized the structure-activity relationship.The results of molecular docking and molecular dynamics simulations pointed out the key amino acid in the binding mode of small molecule drugs and receptor,and analyzed the features in different groups and the inhibition mechanism.We hope these discoveries provide some theoretical support for the design of novel P2Y₁ and P2Y₁₂ receptor inhibitors.Specifically,this paper includes the following parts:In Chapter 1,we introduced the cause and mechanism of thrombus formation and the role of P2Y₁ and P2Y₁₂ receptor in thrombosis.In this chapter,the current experimental and theoretical studies on P2Y₁ and P2Y₁₂ receptor inhibitors and the clinical drugs by inhibiting P2Y₁ and P2Y₁₂ receptor are reviewed.In addition,the basic principles,methods and softwares of computer-aided drug design are also introducted in this paper.In chapter 2,3D-QSAR model,molecular docking and molecular dynamics simulation were imployed to explore the structure-activity interaction of a series of 107 compounds with good inhibitory against P2Y₁₂ receptor.In the 3D-QSAR model,the key structural features were revealed in the Co MFA and Co MSIA model with good statistical significance.In docking analysis,the optimal binding mode of 6-aminonicotinate-based inhibitors in the active pockets and corresponding favorable structure feature were summarized.Finally,molecular dynamics simulation was performed to verify the binding mode of receptor and ligand,and to analyze the effect of different substituents on the binding mode.In chapter 3,29 thienopyridine P2Y₁₂ receptor inhibitors were selected to carry out 3D-QSAR,molecular docking and molecular dynamics simulation studies with the purpose of discovery the structure-activity relationship and the binding mode with P2Y₁₂ receptors.The Co MFA and Co MSIA models in 3D-QSAR are analyzed,and the relationship between their structure and activity is summarized.The results of molecular docking are consistent with the results of 3D-QSAR model,and the binding mode of these moleculars and receptor are analyzed.In the study of molecular dynamics simulation,the key amino acids in the binding mode were pointed out,and the main factors improving the activity were pointed out.In chapter 4,We try to reveal structure-activity relationship and the inhibition mechanism by 3D-QSAR,molecular docking and molecular dynamics simulation for 30 2-?phenoxy-piperidyl?-3-phenylureas moleculars which have good inhibition ability against P2Y₁ receptor.In 3D-QSAR,the structure-activity relationship and the structural modification advices were pointed out by constructing Co MFA and CoMSIA models.In docking analyses,the optimal docking pocket and method were choosen,then analyzing the binding mode of the ligand and the receptor.Finally,the key amino acids and other informations were discussed in the molecular dynamics simulation,and the difference of binding mode in different molecular with different substituents are also discussed in detail.In chapter 5,the main work in the term of postgraduate was summarized and the further prospect was put forward seriously.