Computer-aided Screening Selective Inhibitors Of Phosphodiesterase

Objective:cAMP (cyclic adenosine-3',5'-monophosphate)and cGMP(cyclic guanosine- 3',5'-monophosphate) are ubiquitous second messengers responsible for transducing effects of various extracellular signals, including hormones, light and neurotransmitters. Intracellular concentrations of cAMP and cGMP in tissues are regulated via dynamic equilibrium between their synthesis by adenylyl and guanylyl cyclases and degradation by cyclic nucleotide phosphodiesterases (PDEs) to the physiologically inactive 5' nucleoside monophosphates.PDEs are a superfamily of enzymes. There are now 11 PDE families identified, many of which exist as splice variants. As essential regulators of cyclic nucleotide signaling with diverse physiological functions, PDEs have become recognized as important drug targets for the treatment of various diseases, such as heart failure, depression, asthma, inflammation and erectile dysfunction.With the aim of offering the theoretic information for research and development new PDEs inhibitors, we reviewed the selectivity of PDEs inhibitors.Method:Firstly, we compared the homologous character of sequences of 833 PDEs and 60 crystal structure which have reported. Secondly, based on the PDEs crystal structure, we studied the selectivity of PDEs inhibitors through docking and molecule kinetics. Follow is abstracts of our studies.1. Comparing of amino acid in different sequences.2. Analyzing of PDEs crystal structure3. DockingResult:1. Comparing of amino acid in different sequences.There was more high comparability in sequence in the each PDEs family. Similar comparability exists also among the sequence of 60 PDEs which have crystal structures. So that these crystal structure could represent all natural enzymes.2. Analyzing of PDEs crystal structure Through the review of the difference among congruence ofα-carbon structure of amino acid residues on an active zone, it showed that there was certain diversity between some residues. According to the distribution and congruence of residues at active zone, fifteen structures of PDEs coming from six families will be selected as the models for docking process in followwing study.3. DockingThe compounds with low molecular weight can enter the active pocket easily, and combine steadily. So the compounds which have similar molecular weight should be chosen for docking. After analyzing the result of docking, we find that the PDE inhibitors have selectivity versus their PDE isozymes.Conclude:Through the theoretic study about PDE inhibitors above, we conclude that PDE inhibitors have selectivity versus their PDE isozymes. The method we used is more efficient and economical which can be applicable for other new PDE inghibitors discovery and development programs.