Fig. 1: Strategy for profiling design ideas using free energy perturbation simulations to identify potent molecules, selective for Wee1 over PLK1. | Nature Communications

Fig. 1: Strategy for profiling design ideas using free energy perturbation simulations to identify potent molecules, selective for Wee1 over PLK1.

From: Harnessing free energy calculations for kinome-wide selectivity in drug discovery campaigns with a Wee1 case study

Fig. 1

a Thermodynamic cycle leveraged by ligand-based relative binding free energy calculations (L-RB-FEP+) to estimate the binding affinity of a design idea (orange) (ΔGexptdesign) relative to experimental binding affinity of reference compound (green) (ΔGexptreference) in the crystallographic structure of AZD1775 (compound 1) within the Wee1 binding pocket (gray surface representation; PDB ID 5V5Y47). Arrows A and B represent the alchemical perturbation between the reference and design idea in solvent (ΔGFEPsolvent) and the binding pocket, (ΔGFEPcomplex), respectively, while arrows 1 and 2 represent experimental binding affinities. b Sample schematic of an L-RB-FEP+ profiling cascade to predict potency and selectivity against three off-targets such that only the most promising designs need to be promoted to subsequent stages.

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