Voronkov A E, Baskin I I, Palyulin V A, Zefirov N S
Department of Chemistry, M.V. Lomonosov Moscow State University, 119992 Moscow, Russian Federation.
J Mol Graph Model. 2008 Apr;26(7):1179-87. doi: 10.1016/j.jmgm.2007.10.009. Epub 2007 Nov 9.
Signaling pathways of Wnt-proteins and Fzd-receptors play important role in processes of growth and development of stem cells and in many types of cancers. The binding of the Wnt-proteins and Fzd-receptors is a complicated process, in which 19 Wnt-proteins and 10 Fzd-receptors are involved. Such a large number of combinations of Wnt-Fzd pairs leads to many different influences of Fzd-Wnt-complexes on the development and differentiation of stem cells. The molecular models of xWnt8, hWnt8, mFzd8, hFzd8-proteins and their complexes were constructed and studied in the present work. The amino acids of the binding sites of proteins which participate in these complexes formation and the protein-protein interactions were studied. The pharmacophoric model of the binding site on the xWnt8 and hWnt8-proteins was constructed. In this work we suggested the peptidomimetic ligands, which can be used for the inhibition of the xWnt8-mFzd8 and hWnt8-hFzd8 proteins formation. The de novo design method of Allegrow software was used for the predictions of most prospective functional groups of the peptidomimetic ligands. These ligands can be used as inhibitors of xWnt8-mFzd8 and hWnt8-hFzd8 complex formation and also can be used for drug design by other methods.
Wnt蛋白和Fzd受体的信号通路在干细胞的生长和发育过程以及多种癌症类型中发挥着重要作用。Wnt蛋白与Fzd受体的结合是一个复杂的过程，涉及19种Wnt蛋白和10种Fzd受体。如此大量的Wnt - Fzd对组合导致Fzd - Wnt复合物对干细胞的发育和分化产生许多不同的影响。在本研究中构建并研究了xWnt8、hWnt8、mFzd8、hFzd8蛋白及其复合物的分子模型。研究了参与这些复合物形成的蛋白质结合位点的氨基酸以及蛋白质 - 蛋白质相互作用。构建了xWnt8和hWnt8蛋白上结合位点的药效团模型。在这项工作中，我们提出了肽模拟配体，其可用于抑制xWnt8 - mFzd8和hWnt8 - hFzd8蛋白的形成。使用Allegrow软件的从头设计方法预测肽模拟配体最具前景的官能团。这些配体可用作xWnt8 - mFzd8和hWnt8 - hFzd8复合物形成的抑制剂，也可通过其他方法用于药物设计。
