Novel Small Molecules against Two Binding Sites of Wnt2 Protein as potential Drug Candidates for Colorectal Cancer: A Structure Based Virtual Screening Approach

Document Type : Research article


1 Department and Biotechnology Research Center, Semnan University of Medical Sciences, Semnan, Iran.

2 Department of Molecular Medicine, Pasteur Institute of Iran, Tehran, Iran.


Wnts are the major ligands responsible for activating Wnt signaling pathway through binding to Frizzled proteins (Fzd) as the receptors. Among these ligands, Wnt2 plays the main role in the tumorigenesis of several human cancers especially colorectal cancer (CRC). Therefore, it can be considered as a potential drug target.The aim of this study was to identify potential drug candidates against two binding sites of Wnt2. Structure-based virtual screening approaches were applied to identify compounds against binding sites of Wnt2 for inhibiting the interaction Wnt2 and Fzd receptors. The best hit compounds from molecular docking of National Cancer Institute diversity set II database were used for structural similarity search on ZINC database, obtaining large hit compounds query to perform a virtual screening and retrieving potential lead compounds. Eight lead compounds were selected while their binding affinity, binding modes interactions, and molecular dynamics simulations studies were assessed. Molecular docking studies showed that eight selected lead compounds can bind to the desired binding sites of Wnt2 in a high affinity manner. Bioavailability analysis of the selected lead compounds indicated that they possessed significant drug like properties. Thus, these lead compounds were considered as potential drug candidates for inhibiting Wnt signaling pathway through combining with the binding sites of Wnt2 and hindering the interaction of Wnt2 and Fzd receptors. Our findings suggest that Wnt2 binding sites may be a useful target for treatment for CRC fueling the future efforts for developing new compounds against Wnt signaling pathway.

Graphical Abstract

Novel Small Molecules against Two Binding Sites of Wnt2 Protein as potential Drug Candidates for Colorectal Cancer: A Structure Based Virtual Screening Approach


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