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- W2094171851 abstract "Extracellular signal regulated kinases (ERK1/2) are involved in signaling events that regulate cell division and proliferation. Hyperactivation of ERK has been implicated in the pathogenesis of many human cancers. The F-site recruitment site (FRS) (L198, H230, Y231, L232, L235, and Y261) as well as common docking (CD) (D316 and D319) and ED (T157 and T158) domain in ERK2 is used to facilitate interactions with substrate proteins. Thus, small molecules targeting FRS and/or CD/ED domain have the potential to modulate ERK2 specific functions, potentially leading to the development of novel therapeutic agents. MD simulations of ERK2 from which structurally diverse conformations were selected were used to identify putative binding sites for low molecular weight compounds in the vicinity of the FRS and CD/ED sites. Identified sites were then targeted in individual database screens of over 1.5 million compounds. Following two levels of database screening, fingerprint based similarity clustering and analysis of physicochemical properties that maximize bioavailability, final compounds for biological assay were selected for each site. Inhibition of ERK2-specific phosphorylation was confirmed and dose-dependency was measured in several cancer cell lines using colony survival assays. Direct binding of active compounds to ERK2 was validated by fluorescence quenching experiments. ERK2 was crystallized in complex with several active compounds, showing binding in the critical site in FRS. These identified compounds provide novel tools to study the biological functions of ERK2 as well as act as lead compounds for the development of novel therapeutic candidates for cancer." @default.
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- W2094171851 date "2011-02-01" @default.
- W2094171851 modified "2023-09-26" @default.
- W2094171851 title "Identification of ERK2-Substrate Protein Inhibitors via Virtual Screening, Biological Assays and X-Ray Crystallography" @default.
- W2094171851 doi "https://doi.org/10.1016/j.bpj.2010.12.1382" @default.
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