Virtual Screening And Modification Synthesis Of Novel Antiplatelet Aggregation Drugs Based On The Crystal Structure Of P2Y₁₂ Receptor

Thrombotic disease is one of common cardiovascular disease,which threatens human health severely.The activation,adherence and aggregation of platelet is fairly important in many pathogeny of thrombotic disease,so antiplatelet aggregation has great significance to treat the disease.With the combination of virtual screening(VS)and the experimental drug-synthesis methods,this paper proposed the following methods to select the molecules that are potential to be used as antiplatelet drugs.First,by studying the validity of a series of functions to test the known molecules with antiplatelet reactivity,one can obtain the optimal functions to further screen the 95844 unknown molecules that collected in four drug molecular database,such as TCMD,CNPD,MNPD,MDPI.The 90 molecules selected from the four databases,with the antiplatelet reactivity in the top 30%,were further screened according to Lipinski rules,and two of them were deemed as the potential antiplatelet molecules.Moreover,we focused on designing and synthesizing a series of purine derivatives,using 2-amino-6-chloropurine and 4,6-dichloro-2-propylthio-5-nitropyrimidine as raw materials,with different reaction routes.Finally,14 novel purine derivatives and 8-azapurine derivatives that were not reported in the literature were synthesized,and some of them were tested for their anti-platelet aggregation activity.These compounds have preliminary anticoagulant effects.Finally,the 3D-QSAR analysis among 29 adenine compounds synthesized by predecessors and myself was carried out to find the relationship between purine structure and antiplatelet effect through self-organized molecular field analysis(SOMFA).The optimal model was established,and ross-validation coefficient r2 can reach up to 0.88,the non-cross-validation coefficient r2cv can reach to 0.84,which shows that this model has good selfconsistency and has good prediction ability for activity.At the same time,it finds that the spatial steric factors of substituents are the main influencing factors of activity.The active anticoagulant effect of purine molecules provides guidance.