Harnessing free energy calculations to achieve kinome-wide selectivity in drug discovery campaigns: Wee1 case study

Free energy calculations are revolutionizing early-stage drug-discovery campaigns. Robust free energy methods can rapidly provide accurate on-target and off-target potency predictions to identify promising chemical matter for synthesis, thus, inspiring further rounds of ideation and optimization. Here, we present a free energy framework for efficiently achieving kinome-wide selectivity that led to the discovery of novel selective Wee1 kinase inhibitors. With ligand-based relative binding free energy calculations, multiple novel promising scaffolds were rapidly identified. With protein residue mutation free energy calculations that perturbed the Wee1 gatekeeper residue, off-target liabilities across the kinome of these promising series were efficiently reduced. With judicious identification of a selectivity handle, applying this computational strategy could effectively streamline the optimization of on-target and off-target profiles, thereby accelerating drug discovery timelines and decreasing unanticipated off-target toxicities.