Development of inhibitors of TCF/β-catenin complex and their validation using Molecular Modeling techniques

Abstract

The Wnt signalling pathway plays a vital role in cell proliferation and hence plays a crucial role in the embryonic development stage of the cells. This pathway is usually inactive in well grown cells. But, it is seen that in cancerous cell lines, especially colorectal cancer cells, the Wnt signalling pathway is active, due to which there is an increased concentration of the protein β-catenin in the cell. Β-catenin then enters the nucleus and replaces the groucho protein, to interact with T-Cell Factor. This complex acts as a transcriptional activator and hence leads to cell proliferation. Given the importance of discovering strategies to inhibit this pathway, one of the important ways of achieving this is to inhibit the β-catenin/TCF complex. There are a number of commercially available molecules that are known to inhibit this complex but there are not enough computational studies that demonstrate the binding affinities of these molecules to the different “Hotspots” present in this complex. The goal of this project was to calculate the free-energy of interactions for different molecules, some known and some newly designed, and compare them to get a quantitative idea about the binding affinities. The calculations showed that the molecule BC2 has a great affinity towards “Hotspot 2” when compared to BC1 and BC4, where BC1, BC2 and BC4 are molecules that were newly designed. The free-energy of BC2 molecule was found to be very similar to CHEMBL1334062, a commercially known inhibitor.