An efficient and rational method for selecting allosteric modulators to GABAA receptors using ligand-directed chemistry

摘要

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 protein1. 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 despite having the risk of their drug resistance and addiction2.