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Charles Sader, Jie J Zheng; Correlating computed binding affinities of Wnt inhibitors with structural perturbation of the Dishevelled PDZ active site. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4609.
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© ARVO (1962-2015); The Authors (2016-present)
Aberrant Wnt signaling has been implicated as a cause of elevated pressure in the eye, a well-known risk factor for glaucoma. Dishevelled, a cytoplasmic protein involved in the Wnt signaling pathway, is a major regulator of development through control of cellular functions such as proliferation and differentiation. Inhibition of abnormal Wnt signaling by targeting the Dvl PDZ domain has therapeutic potential; however, improvement of binding affinity of small-molecule inhibitors has been a challenge. The purpose of this study was to develop a quantitative structure-activity relationship based on small-molecule and peptide ligands with affinities in the micromolar range that can be used for rational design of higher potency drugs.
Structures of Dvl co-crystallized with each ligand were obtained from the Protein Data Bank and then subsequently optimized for MD simulations using the Schrödinger software. 20 nanosecond molecular dynamics (MD) simulations of the Dvl PDZ domain in the apo and holo states were performed using OPLS3 force field parameters in explicit SPC water. Statistical analyses and distance distributions were plotted using the Prism software. Binding free energies were calculated using the molecular mechanics Poisson Boltzmann surface area method within AMBER.
Equilibrium MD trajectories show an increase of more than 3 Å in the pairwise distances of S265-L321 positions upon ligand binding. Distributions of five additional distances along the active site "binding groove" (G263-V325, I264-R322, I266-V318, V267-A317, and G268-D315) have mean values that vary by about 2-4 Å and are ligand-dependent. Our analysis reveals changes in backbone dihedral angles and computed degree of secondary structure that support distortion toward a concave active site upon binding.
The observed structural deviations from apo upon binding correlate with computed binding affinities for each ligand. Upon binding, the apparent "opening" of the binding groove is significant and is not sampled in the apo protein. This suggests that an induced fit model more closely describes binding to the Dvl PDZ domain than does a conformational selection model.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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