| P2Y12 receptor,a typical platelet receptor,is a target for the treatment of thrombosis.In this research,The crystal structure of P2Y12 receptor(PDB:4PXZ)and its interaction models with drug molecule were studied,and the influencing factors of drug molecule structure on drug activity were sumamaried.Then the 3-Dimensions structure-activity relationships of 45 adenosine compounds were studied using CoMFA,CoMSIA and SOMFA methods.Based on the conclusions of the interaction models and 3D-QSAR between the structure of P2Y12 receptor and the molecular structure-activity of adenosine drugs,the regular patterns of the structure of adenosine compounds influence on the drug activity were obtained:an aromatic primary amine with high steric resistance and electron cloud density at C-6 position of purine,increasing the electron cloud density of covalent bond between aromatic ring and N atom at C-6 positon of purine,increasing the number of-OH of ribose ring and-SPr at C-2 position of purine could increase the activity.These theoretical basis could be provided for designing novel drug molecules with drug activity.Based on the above theoretical basis,20 new compounds were designed.This series of 6-substituted Schiff base 8-aza adenosine derivatives with aromatic ring and C=N double bond conjugated structure were synthesized from pyrimidine and furan ribose in six steps.Catalytic hydrogenation and other reactions involved in the synthesis process ensured the yield of products,and the total yield of some compounds reached 51%.The structures of the synthesized compounds were characterized.Their activity was predicted by using 3D-QSAR optimal model.The predicted results show that the new compounds maybe have good activity. |
