title: Molecular modeling of modified peptides, potent inhibitors of the xWNT8 and hWNT8 proteins.
abstract: 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.
authors.affiliation: Department of Chemistry, M.V. Lomonosov Moscow State University, 119992 Moscow, Russian Federation. voronkov@org.chem.msu.su
authors.forename: A E
authors.initials: AE
authors.lastname: Voronkov
authors.forename: I I
authors.initials: II
authors.lastname: Baskin
authors.forename: V A
authors.initials: VA
authors.lastname: Palyulin
authors.forename: N S
authors.initials: NS
authors.lastname: Zefirov
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D017076:Computer-Aided Design; D015195:Drug Design; D051157:Frizzled Receptors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism; D012984:Software; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D014981:Xenopus; D029867:Xenopus Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D051157:Frizzled Receptors; D008024:Ligands; D010455:Peptides; D043562:Receptors, G-Protein-Coupled; D051153:Wnt Proteins; D029867:Xenopus Proteins; C511610:Fzd8 protein, mouse; C495248:wnt8a protein, Xenopus