||An efficient and rational method for selecting allosteric modulators to GABAA receptors using ligand-directed chemistry
Yamaura, Kei ,
Kiyonaka, Shigeki ,
Sakamoto, SeijiHamachi, Itaru
Allosteric modulators have drawn intense attention because of their high specificity and low toxicity relative to traditional compounds which bind to the orthosteric site of a target protein. However, it is hard to discover such allosteric modulators acting on membrane-proteins, important drug targets. As a result, development of these modulators has been stagnant in recent years. For example, benzodiazepines, allosteric modulators acting on GABAA receptors, are widely and clinically utilized as anxiolytic and sleep-inducing agents in spite of their drug resistance and addiction. Here, we developed a new method termed BFQRAP (Bimolecular Fluorescence Quenching and Recovery with Assistance of Positive allosteric modulator) using GABAAR-based semisynthetic fluorescent biosensors constructed by ligand-directed chemistry, which enables to rationally detect and select positive allosteric modulators that is bound to various allosteric sites of GABAAR. This method was applied to the high-throughput screening of a chemical library, leading to the discovery of new positive allosteric modulators functioning on GABAARs.
日本化学会 第98春季年会 (2018)