부산대학교 도서관

Forward-synthetic databases are an efficient way to enumerate chemical space. We explored here whether these databases are good sources of novel protein ligands and how many molecules are obtainable and in which time frame. Based on docking calculations, series of molecules were selected to gain insights into the ligand structure-activity relationship. To evaluate the novelty of compounds in a challenging way, we chose the [[beta].sub.2]-adrenergic receptor, for which a large number of ligands is already known. Finding dissimilar ligands is thus the exception rather than the rule. Here we report on the results, the successful synthesis of 127/240 molecules in just 2 weeks, the discovery of previously unreported dissimilar ligands of the [[beta].sub.2]-adrenergic receptor, and the optimization of one series to a [K.sub.D] of 519 nM in only one round. Moreover, the finding that only 3 of 240 molecules had ever been synthesized before indicates that large parts of chemical space are unexplored. de novo design | parallel synthesis | highly designed libraries | docking | forward synthetic libraries