| The serotonin receptor subtype 1A (5-HT1AR) has long been one of the most important targets for central nervous system (CNS) diseases, and potent 5-HT1AR agonists have high therapeutic potentials for the treatment of depression, anxiety, schizophrenia, Parkinson’s diseases, neurogenesis and stroke. Although plenty of 5-HT1AR agonists have been reported, most were originated from several widely studied structural classes and promising new chemical entities are really rare. Thus, it is meaningful to explore high-affinity and high-selectivity 5-HT1AR agonists with novel scaffolds. In this study, we first gave an overview on methods, strategies and recent advances of computer-aided drug design (CADD). Then we described the discovery of novel 5-HT1AR agonists and the investigation of activation mechanism of 5-HT1AR through CADD approach.A homology model of 5-HT1AR was built based on the latest released high-resolution crystal structure of the beta-2 adrenergic receptor (β2AR) in its active state (PDB: 3SN6), and a dynamic pharmacophore model was constructed by integrating molecular docking, molecular dynamics simulation and active site analysis.10 novel 5-HT1AR agonists displaying medium to high affinities were finally obtained after we administered step-by-step screening strategy, i.e. screen by drug-like rules, dynamic pharmacophore-based virtual screening, docking-based virtual screening and bioassay screening. Among them, FW01 (Ki= 51.9 nM,EC50= 7 nM) was evaluated as the strongest agonist for 5-HT1AR. Based the analyses of molecular dynamics simulation results and available experimental data, we further investigated the binding mode of FW01 with 5-HT1AR and a stepwise 5-HT1AR signal transduction model induced by agonist FW01 was proposed.With the rapid development of computer science and ever growing computer power, accurate quantum chemistry calculation is more and more popular in CADD area and takes a significant role in drug discovery process. In chapter 3, we studied the conversion between two naturally stable conformers of (-)-meptazinol hydrochloride in solution via ab initio calculations. The results are in good agreement with our NMR observation and helped us draw a conclusion that the pharmacophoric conformer of (-)-meptazinol might originate from the conformer with less favorable energy rather than that with the lowest energy.Another application of CADD after lead identification is lead optimization. In last section, we briefly introduced the rational design of indolebutylamines derivatives as novel selective D3R ligands. With the aid of molecular docking, we obtained compound 11q which exhibits ca.20-fold higher binding affinity for D3R than the lead compound. |
