Rational Drug Design Of Three GPCRs Related To Neurodegenerative Diseases

The incidence of neurodegenerative diseases increased with age,such as Alzheimer's disease and Parkinson's disease.The aging population is growing which makes drug discovery for such diseases significant in China.GPCRs are important targets for neurological diseases,but it is difficult to obtain the three-dimensional?crystal?structure of GPCR.So this paper was set to provide a valid structural information,to explore the mechanism and finally to design ligands of GPCRs.Galanin receptor type 2,cannabinoid receptor 2 and GPR17 are three neurodegenerative disease-related GPCRs.The main idea of this paper consists of homology modeling of the receptor,docking with endogenous ligand to study mechanisms and virtual screening the chemical library to get new skeletal structures.The model of galanin receptor type 2 was established by using opioid receptor(PDB: 4N6H)as a template.It proved that Ile1053.32,Met1093.36,Tyr1604.60,Tyr163 and Arg2747.35 were the key amino acids in ligand binding and Pocket ?I which was made of TM2,TM3,ECL2 and ECL3 was the most favorable allosteric site based on molecular docking and molecular dynamics simulation.Being conjuncted with CYM2503 would result in blocking the binding of sodium ions or affecting the pathway of sodium ions.This is the first report to discuss the modes of allosteric modulators in the area of GALR2.Virtual screening for the orthosteric site and the allosteric site based on previous researches helps to get new ligands.Our research would be helpful for drug discovery well as mechanisms.Six compounds were selected to test their biological activity after homology modeling of cannabinoid receptor 2 and virtual screening within the chemical library which contains 3000 ‘drug-like' low-molecular-weight compounds.CYC-YX-2102(compound name)showed to be the most valuable among the six compounds(Ki = 0.35 ?M).On the basis of molecular docking,we designed new ligands with independent intellectual property rights which may show high affinity and high selectivity.Homology modeling of GPR17 was accomplished with the template P2Y1(PDB: 4XNV).Molecular docking studied the interaction between GPR17 and UDP,which suggested Arg3087.35 to be the essential amino acid.Possible active compounds were obtained by virtual screening.We also analyzed the binding mode of compound CYC-FX-3120 and GPR17 because of its high docking score.