In silico drug discovery of Wnt signaling small molecule agonists and antagonists for normal and cancer stem cells

The studies of adult stem cells and stem cell niches regulation signals are among cutting edge research in modern molecular biology. The emerging field of research is devoted to the concept of "cancer stem cells" in which the lost of control on stem cells proliferation is considered as one of the causes for human cancer chemotherapy resistance and metastasis. The Wnt and Shh signaling pathways play an important role in regulation of differentiation, proliferation and cancer transformation of adult stem ce lls. Although there are series of known agonists and antagonists for Wnt and Shh signaling pathways there is lack of knowledge on molecular mechanisms of these small molecules action. Such knowledge is required for successful drug development process. Mol ecular modeling and QSAR methods are among the most effective approaches for development of biologically active compounds with new mechanisms of action, improved activity and optimized ADME/Tox properties. Molecular modeling enables detailed understanding of drug-protein interactions required for small molecules chemical structure optimization. Another important challenge is related to tissue selectivity of designed small molecule compounds for treatment of cancer (antagonists) and degenerative diseases (agonists). Frizzled receptors family members vary significantly in tissue distribution which makes them interesting biotargets. The CRD-domain of Frizzled receptors is required for interaction with Wnt proteins. The preliminary work shows the possibility of small molecules drug design for the binding site on CRD domain. The goal of the proposed research is to discover drug-like compounds, which can selectively bind different Frizzled receptors and act both as agonists and antagonists of Wnt signaling pat hway. The proposed work is planned to be performed in one of leading norwegian groups on stem cells research with close interaction and cross-validation between theoretical modeling and the experiment methods.