Defining scaffold geometries for interacting with proteins: Geometrical classification of secondary structure linking regions

Medicinal chemists synthesize arrays of molecules by attaching functional groups to scaffolds. There is evidence suggesting that some scaffolds yield biologically active molecules more than others, these are termed privileged substructures. One role of the scaffold is to present its side-chains for molecular recognition, and biologically relevant scaffolds may present side-chains in biologically relevant geometries or shapes. Since drug discovery is primarily focused on the discovery of compounds that bind to proteinaceous targets, we have been deciphering the scaffold shapes that are used for binding proteins as they reflect biologically relevant shapes. To decipher the scaffold architecture that is important for binding protein surfaces, we have analyzed the scaffold architecture of protein loops, which are defined in this context as continuous four residue segments of a protein chain that are not part of an alpha-helix or beta-strand secondary structure. Loops are an important molecular recognition motif of proteins. We have found that 39 clusters reflect the scaffold architecture of 89% of the 23,331 loops in the dataset, with average intra-cluster and inter-cluster RMSD of 0.47 and 1.91, respectively. These protein loop scaffolds all have distinct shapes. We have used these 39 clusters that reflect the scaffold architecture of protein loops as biological descriptors. This involved generation of a small dataset of scaffold-based peptidomimetics. We found that peptidomimetic scaffolds with reported biological activities matched loop scaffold geometries and those peptidomimetic scaffolds with no reported biologically activities did not. This preliminary evidence suggests that organic scaffolds with tight matches to the preferred loop scaffolds of proteins, implies the likelihood of the scaffold to be biologically relevant

Phyto-polyphenols as potential inhibitors of breast cancer metastasis

Abstract Breast cancer is the most common cancer among women as metastasis is currently the main cause of mortality. Breast cancer cells undergoing metastasis acquire resistance to death signals and increase of cellular motility and invasiveness. Plants are rich in polyphenolic compounds, many of them with known medicinal effects. Various phyto-polyphenols have also been demonstrated to suppress cancer growth. Their mechanism of action is usually pleiotropic as they target multiple signaling pathways regulating key cellular processes such as proliferation, apoptosis and differentiation. Importantly, some phyto- polyphenols show low level of toxicity to untransformed cells, but selective suppressing effects on cancer cells proliferation and differentiation. In this review, we summarize the current information about the mechanism of action of some phyto-polyphenols that have demonstrated anti-carcinogenic activities in vitro and in vivo. Gained knowledge of how these natural polyphenolic compounds work can give us a clue for the development of novel anti-metastatic agents