Structure-Activity Correlation Relationship Of Phosphodiesterase-2Inhibitors

cAMP and cGMP are the intracellular molecules that can transmit intracellular messenger, known as intracellular second messenger. They plays an important role in many aspects of metabolism, neurotransmission and cell growth. The concentration lev-els of cAMP and cGMP is controlled by synthesis of adenosine cyclase and degradation of phosphodiesterase. Phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP, and generating no activity AMP and GMP. Therefore, phosphodiesterase play an important regulatory role on cAMP and cGMP. In the family of11kinds of phos-phodiesterase isozymes, PDE2has became popular targets because it has dual selectivity for cAMP and cGMP, and its inhibitors can enhance memory and improve aspects of endothelial cell permeability. This paper focuses on the study of phosphodiesterase2in-hibitors, using some Computer-Aided Drug Design methods, such as QSAR and Molec-ular Docking, start with the analysis of the binding mode of mang reported PDE2inhibi-tors and the crystal structure of the catalytic domain PDE2. The paper are exploring the PDE2inhibitors’ quantitative structure activity relationships, which can improve effec-tive information for the future design of new PDE2inhibitors.The first chapter summarizes the PDE enzymes and their inhibitors’ new research progress. In the second chapter we studies the benzo[1,4]diazepine-2-one derivatives with comparative molecular field analysis (CoMFA). In the research process, we improve the prediction ability of the CoMFA with all-orientation search(AOS). We found that three-dimensional field of small molecule active greater impact than electrostatic field. Reduce benzo[1,4]diazepine-2-one derivatives’ R3group volume may increase the activ-ity of small molecules.In the third chapter, we set99compounds PDE2inhibitors struc-ture as the research object, using the method combining of molecular docking and multi-ple linear regression (MLR), study the PDE2inhibitors’ correlation relationship between structure and activity. We design a new kind of method which can predict the PDE2in-hibitors’ activity, and it can apply to the compound of different ring structure. The meth-od can provide guidance for future forecasting and design of new highly active PDE2inhibitor.