Evolution of Drug Discovery Targeting for G-protein Coupled Receptors

点击翻译按钮获取中文摘要

In recent drug discovery researches, rational drug design is one of principal approaches to develop pharmaceutical agents. Recent progressive structural analyses of enzyme-substrate or receptor-ligand complex by X-ray crystallography have practically contributed to the inhibitor or antagonist designs. With increase in numbers of disclosed natural and unnatural peptide ligands from genome/proteome researches, this technique is increasingly expected to be an attractive methodology to find out lead compounds rationally, as well as random screening. Meanwhile, in the case of membrane protein ligands, it is much more difficult to assume what functional groups could be the pharmacophore, because exact structure analyses of these complexes are not available. In this program, we have engaged in evolutional development of technology for G-protein-coupled receptors, which are one of the major targets for recent drug discovery, including (1) establishment of chemical synthetic methodology for membrane proteins; (2) development of specific GPR54 ligands and the rational down-sizing; (3) development of efficient strategy for the preparation of non-peptide ligands.