Accelerated Discovery of Novel Benzodiazepine Ligands
by Experiment-Guided Virtual Screening
- Publication date
- Publisher
Abstract
High throughput discovery
of ligand scaffolds for target proteins
can accelerate development of leads and drug candidates enormously.
Here we describe an innovative workflow for the discovery of high
affinity ligands for the benzodiazepine-binding site on the so far
not crystallized mammalian GABA<sub>A</sub> receptors. The procedure
includes chemical biology techniques that may be generally applied
to other proteins. Prerequisites are a ligand that can be chemically
modified with cysteine-reactive groups, knowledge of amino acid residues
contributing to the drug-binding pocket, and crystal structures either
of proteins homologous to the target protein or, better, of the target
itself. Part of the protocol is virtual screening that without additional
rounds of optimization in many cases results only in low affinity
ligands, even when a target protein has been crystallized. Here we
show how the integration of functional data into structure-based screening
dramatically improves the performance of the virtual screening. Thus,
lead compounds with 14 different scaffolds were identified on the
basis of an updated structural model of the diazepam-bound state of
the GABA<sub>A</sub> receptor. Some of these compounds show considerable
preference for the α<sub>3</sub>β<sub>2</sub>γ<sub>2</sub> GABA<sub>A</sub> receptor subtype