Abstract
One of the remaining bottlenecks in fragment-based drug design (FBDD) is the initial exploration and optimization of the identified hit fragments. There is a growing interest in computational approaches that can guide these efforts by predicting the binding affinity of newly designed analogues. Among others, alchemical free energy (AFE) calculations promise high accuracy at a computational cost that allows their application during lead optimization campaigns. In this review, we discuss how AFE could have a strong impact in fragment evolution, and we raise awareness on the challenges that could be encountered applying this methodology in FBDD studies.
Original language | English |
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Pages (from-to) | 36-42 |
Number of pages | 7 |
Journal | Drug Discovery Today: Technologies |
Volume | 40 |
Early online date | 18 Nov 2021 |
DOIs | |
Publication status | Published - Dec 2021 |
Bibliographical note
Funding Information:This research was funded by European Union's Horizon 2020 MSCA Program under grant agreement 675899 [FRAGNET]. We would like to thank F. Moraca and R. Abel for a much appreciated collaboration.
Funding Information:
The authors declare no conflict of interest. This research was funded by European Union’s Horizon 2020 MSCA Program under grant agreement 675899 [FRAGNET].
Publisher Copyright:
© 2021
Keywords
- Computer-aided drug design
- Fragment-based drug design
- Free energy perturbation
- Molecular dynamics
- Relative binding free energy