Experiment‐guided virtual screening provides new high affinity ligands for the benzodiazepine site on GABA‐A receptors (654.4)

Abstract

Often novel high affinity ligands are required for a well‐established target protein. Reasons include side effects, resistance development to or sub‐optimal pharmacokinetic or pharmacodynamic properties of an established drug. Here we describe the identification of 19 compounds (14 different scaffolds) that are high affinity ligands for the benzodiazepine‐binding site on mammalian GABA‐A receptors, hitherto un‐crystallized proteins. The procedure includes biochemical techniques that may be generally applied to other proteins. Prerequisites are a ligand that can be chemically modified with cysteine‐reactive groups, knowledge on amino acid residues contributing to the binding pocket on the protein and either crystal structures of proteins homologous to the target protein or even better a crystal structure of the target itself. The procedure includes virtual screening that when used without additional techniques often only results in low affinity ligands, even when a crystal structure of the target protein is available. Combination of crystallization with a functional approach may replace the use of crystallization alone in efforts towards finding new high affinity ligands of an established target.Grant Funding Source: Supported by Swiss National Science Foundation grant 31003A‐132806/1 to E.S.