bei Google ScholarTitelangaben
Sun, Shan ; Fushimi, Makoto ; Rossetti, Thomas ; Kaur, Navpreet ; Ferreira, Jacob ; Miller, Michael ; Quast, Jonathan ; van den Heuvel, Joop ; Steegborn, Clemens ; Levin, Lonny R. ; Buck, Jochen ; Myers, Robert W. ; Kargman, Stacia ; Liverton, Nigel ; Meinke, Peter T. ; Huggins, David J.:
Scaffold Hopping and Optimization of Small Molecule Soluble Adenyl Cyclase Inhibitors Led by Free Energy Perturbation.
In: Journal of Chemical Information and Modeling.
Bd. 63
(2023)
Heft 9
.
- S. 2828-2841.
ISSN 1549-960X
DOI: https://doi.org/10.1021/acs.jcim.2c01577
Abstract
Free energy perturbation is a computational technique that can be used to predict how small changes to an inhibitor structure will affect the binding free energy to its target. In this paper, we describe the utility of free energy perturbation with FEP+ in the hit-to-lead stage of a drug discovery project targeting soluble adenyl cyclase. The project was structurally enabled by X-ray crystallography throughout. We employed free energy perturbation to first scaffold hop to a preferable chemotype and then optimize the binding affinity to sub-nanomolar levels while retaining druglike properties. The results illustrate that effective use of free energy perturbation can enable a drug discovery campaign to progress rapidly from hit to lead, facilitating proof-of-concept studies that enable target validation.
Weitere Angaben
| Publikationsform: | Artikel in einer Zeitschrift |
|---|---|
| Begutachteter Beitrag: | Ja |
| Institutionen der Universität: | Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Chemie > Lehrstuhl Biochemie > Lehrstuhl Biochemie I - Proteinbiochemie der Signaltransduktion - Univ.-Prof. Dr. Clemens Steegborn |
| Titel an der UBT entstanden: | Ja |
| Themengebiete aus DDC: | 500 Naturwissenschaften und Mathematik > 540 Chemie |
| Eingestellt am: | 21 Aug 2023 06:00 |
| Letzte Änderung: | 21 Aug 2023 06:00 |
| URI: | https://eref.uni-bayreuth.de/id/eprint/86603 |