SAR-Guided Scoring Function and Mutational Validation Reveal the Binding Mode of CGS-8216 at the α1+/γ2- Benzodiazepine Site.
In: Journal of chemical information and modeling, Jg. 58 (2018-08-27), Heft 8, S. 1682-1696
academicJournal
Zugriff:
The structural resolution of a bound ligand-receptor complex is a key asset to efficiently drive lead optimization in drug design. However, structural resolution of many drug targets still remains a challenging endeavor. In the absence of structural knowledge, scientists resort to structure-activity relationships (SARs) to promote compound development. In this study, we incorporated ligand-based knowledge to formulate a docking scoring function that evaluates binding poses for their agreement with a known SAR. We showcased this protocol by identifying the binding mode of the pyrazoloquinolinone (PQ) CGS-8216 at the benzodiazepine binding site of the GABA A receptor. Further evaluation of the final pose by molecular dynamics and free energy simulations revealed a close proximity between the pendent phenyl ring of the PQ and γ2D56, congruent with the low potency of carboxyphenyl analogues. Ultimately, we introduced the γ2D56A mutation and in fact observed a 10-fold potency increase in the carboxyphenyl analogue, providing experimental evidence in favor of our binding hypothesis.
Titel: |
SAR-Guided Scoring Function and Mutational Validation Reveal the Binding Mode of CGS-8216 at the α1+/γ2- Benzodiazepine Site.
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Autor/in / Beteiligte Person: | Siebert, DCB ; Wieder, M ; Schlener, L ; Scholze, P ; Boresch, S ; Langer, T ; Schnürch, M ; Mihovilovic, MD ; Richter, L ; Ernst, M ; Ecker, GF |
Zeitschrift: | Journal of chemical information and modeling, Jg. 58 (2018-08-27), Heft 8, S. 1682-1696 |
Veröffentlichung: | Washington, D.C. : American Chemical Society, c2005-, 2018 |
Medientyp: | academicJournal |
ISSN: | 1549-960X (electronic) |
DOI: | 10.1021/acs.jcim.8b00199 |
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