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Harnessing free energy calculations for kinome-wide selectivity in drug discovery campaigns with a Wee1 case study
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Journal Article
Harnessing free energy calculations for kinome-wide selectivity in drug discovery campaigns with a Wee1 case study
2025
Overview
Optimizing both on-target and off-target potencies is essential for developing effective and selective small-molecule therapeutics. Free energy calculations offer rapid potency predictions, usually within hours and with experimental accuracy and thus enables efficient identification of promising compounds for synthesis, accelerating early-stage drug discovery campaigns. While free energy predictions are routinely applied to individual proteins, here, we present a free energy framework for efficiently achieving kinome-wide selectivity that led to the discovery of selective Wee1 kinase inhibitors. Ligand-based relative binding free energy calculations rapidly identified multiple novel potent chemical scaffolds. Subsequent protein residue mutation free energy calculations that modified the Wee1 gatekeeper residue, significantly reduced their off-target liabilities across the kinome. Thus, with judicious use of this gatekeeper residue selectivity handle, applying this computational strategy streamlined the optimization of both on-target and off-target potencies, offering a roadmap to expedite drug discovery timelines by decreasing unanticipated off-target toxicities.
Free energy calculations are an essential tool to identify targets for individual proteins. Here, authors describe free energy perturbation (FEP+) calculations to optimise on target and off-target potencies for the discovery of potent Wee1 inhibitors with kinome-wide selectivity.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ Cell Cycle Proteins - antagonists & inhibitors
/ Cell Cycle Proteins - chemistry
/ Cell Cycle Proteins - genetics
/ Cell Cycle Proteins - metabolism
/ Energy
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Ligands
/ Mutation
/ Nuclear Proteins - antagonists & inhibitors
/ Nuclear Proteins - chemistry
/ Nuclear Proteins - metabolism
/ Protein Kinase Inhibitors - chemistry
/ Protein Kinase Inhibitors - pharmacology
/ Protein-Tyrosine Kinases - antagonists & inhibitors
/ Protein-Tyrosine Kinases - chemistry
/ Protein-Tyrosine Kinases - genetics
/ Protein-Tyrosine Kinases - metabolism
/ Proteins
/ Residues
/ Science
/ Solvents
