Accelerated discovery of novel benzodiazepine ligands by experiment-guided virtual screening.

Middendorp, Simon; Puthenkalam, Roshan; Baur, Roland; Ernst, Margot; Sigel, Erwin (2014). Accelerated discovery of novel benzodiazepine ligands by experiment-guided virtual screening. ACS Chemical Biology, 9(8), pp. 1854-1859. American Chemical Society 10.1021/cb5001873

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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 GABAA 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 GABAA receptor. Some of these compounds show considerable preference for the α3β2γ2 GABAA receptor subtype.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Middendorp, Simon; Baur, Roland and Sigel, Erwin

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1554-8929

Publisher:

American Chemical Society

Language:

English

Submitter:

Barbara Järmann-Bangerter

Date Deposited:

01 Apr 2015 13:04

Last Modified:

02 Sep 2015 10:22

Publisher DOI:

10.1021/cb5001873

PubMed ID:

24960548

BORIS DOI:

10.7892/boris.65698

URI:

https://boris.unibe.ch/id/eprint/65698

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