Discovery of Selective Ligands for GPCRs and related Receptors

다국어 초록 (Multilingual Abstract)

Since the concept of combinatorial chemistry was introduced and technologies for combinatorial chemistry were developed, many successful combinatorial libraries were developed based on the privileged structures of ligands for G-Protein Coupled Receptors(GPCR) and related channel blockers owing to the membrane bound nature of these receptors and similarities in three dimensional structures.
Based on this idea we have developed combinatorial libraries of piperazinyl alkyl heterocyclic compounds and related structures, and identified compounds for selective binding to dopamine receptors, serotonin receptors and calcium channels with excellent subtype selectivity.
These sets of compounds provided good structure activity relationships and offered clues to identification of pharmacophores of the receptors.
These information were used in identifying new ligand structures for receptor binding through comparative molecular field anaylsis(CoMFA) and comparative molecular similarity indexes analysis(CoMSIA). For example, a set of 24 structurally similar compounds served to establish a model. Four different conformations of the most active compound that were obtained from Catalysis pharmacophore modeling and SYBYL random search option, were used as the template structures for the alignment. All CoMFA and CoMSIA models gave cross-validated r2(q2) values of more than 0.5 and conventional r2 value of more than 0.85. The predictive ability of the models was validated by an external test set of 10 compounds. They gave satisfactory r2 values ranging from 0.577 to 0.866 for all models. CoMFA and CoMSIA contour maps were used to analyze the structural features of the ligands accounting for the activity in terms of positively contributing physicochemical properties. Based on this analysis and validation process, a three dimensional pharmacophore models were defined and successfully used to identify several new structures for selective binding to receptors.