Fig. 2: Strategy for identifying novel kinome-wide selective Wee1 inhibitors. | Nature Communications

Fig. 2: Strategy for identifying novel kinome-wide selective Wee1 inhibitors.

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

Fig. 2

a Thermodynamic cycle leveraged by protein residue mutation free energy calculations (PRM-FEP+) calculations to estimate the binding affinity of a design idea (gray, surface rendering) bound to the wild-type sequence (ribbon + green CPK) (ΔGexptWT) compared to the mutant sequence (ribbon + orange CPK) (ΔGexptmutant) of the Wee1 binding pocket (PDB ID: 5V5Y47). Arrows A and B represent the alchemical perturbation between the wild-type and mutant sequence in solvent (ΔGFEPsolvent) and the binding pocket (ΔGFEPcomplex), respectively, while arrows 1 and 2 represent experimental binding affinities. b Sample schematic of profiling cascade combining ligand-based relative binding free energy calculations (L-RB-FEP+) and protein residue mutation free energy calculations (PRM-FEP+) to identify potent and selective inhibitors efficiently.

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