Wnt/beta-catenin signaling is critical for cell growth and development, with its hyperactive dysregulation implicated in the development of cancer. Current therapeutic research on inhibition of Wnt/beta-catenin signaling is impeded by the high cost of experimentally determining binding affinities. Consequently, interest has risen in screening potential inhibitors binding affinities with computational tools to reduce costs. Here, we test the validity of a computational molecular dynamics simulator, Binding Free Energy Estimator 2 (BFEE2), in determining peptide and small molecule ligand affinity for Wnt/beta-catenin signaling. We focus on the Dishevelled (DVL) PDZ domain, a key mediator in WNT signaling through its ability to bind to various peptide ligands. We analyze the binding affinities of several DVL PDZ domain-peptide complexes against previously established results to determine the validity of computational analysis. We conclude that computational molecular dynamics simulations are moderately effective in determining DVL peptide ligand complex affinity with an R2 of 0.44; however, the simulation was not effective with small molecule drug inhibitors with an R2 of 0.06.
Singh et al. (Sun,) studied this question.