at Google ScholarTitle data
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.
Vol. 63
(2023)
Issue 9
.
- pp. 2828-2841.
ISSN 1549-960X
DOI: https://doi.org/10.1021/acs.jcim.2c01577
Abstract in another language
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.
Further data
| Item Type: | Article in a journal |
|---|---|
| Refereed: | Yes |
| Institutions of the University: | Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry > Chair Biochemistry - Univ.-Prof. Dr. Clemens Steegborn |
| Result of work at the UBT: | Yes |
| DDC Subjects: | 500 Science > 540 Chemistry |
| Date Deposited: | 21 Aug 2023 06:00 |
| Last Modified: | 21 Aug 2023 06:00 |
| URI: | https://eref.uni-bayreuth.de/id/eprint/86603 |