Prediction of Structure of Human WNT-CRD (FZD) Complex for Computational Drug Repurposing

The observed genetic alterations of various extracellular and intracellular WNT (Wingless, Int-1 proto-oncogene) signaling components can result in an increase or decrease in gene expression, and hence can be obstructed proficiently. These genetics target sites may include the prevention of WNT-FZD (Frizzled) binding, destruction of beta-catenin and formation of Axin, APC and GSK-3 beta complex. Hence, the localized targeting of these interacting partners can help in devising novel inhibitors against WNT signaling. Our present study is an extension of our previous work, in which we proposed the coregulated expression pattern of the WNT gene cluster (WNT-1, WNT-6, WNT-10A and WNT-10B) in human breast carcinoma. We present here the computationally modeled three dimensional structure of human WNT-1 in complex with the FZD-1 CRD (Cysteine Rich Domain) receptor. The dimeric cysteine-rich domain was found to fit into the evolutionarily conserved U-shaped groove of WNT protein. The two ends of the U-shaped cleft contain N-terminal and C-terminal hydrophobic residues, thus providing a strong hydrophobic moiety for the frizzled receptor and serving as the largest binding pocket for WNT-FZD interaction. Detailed structural analysis of this cleft revealed a maximum atomic distance of similar to 28 angstrom at the surface, narrowing down to similar to 17 angstrom and again increasing up to similar to 27 angstrom at the bottom. Altogether, structural prediction analysis of WNT proteins was performed to reveal newer details about post-translational modification sites and to map the novel pharmacophore models for potent WNT inhibitors.