Progress in Free Energy Perturbation: Options for Evolving Fragments

Lorena Zara, Nina Louisa Efrém, Jacqueline E. van Muijlwijk-Koezen, Iwan J.P. de Esch, Barbara Zarzycka*

*Corresponding author for this work

Research output: Contribution to JournalReview articleAcademicpeer-review

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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 languageEnglish
Pages (from-to)36-42
Number of pages7
JournalDrug Discovery Today: Technologies
Volume40
Early online date18 Nov 2021
DOIs
Publication statusPublished - 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

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