Chemical marks on histones, collectively called the histone code, are involved in regulation of gene expression, cell cycle and genome stability. Proteins that mediate the histone signaling by binding to the histone marks constitute a largely untapped source of therapeutic targets. The Center for Integrative Chemical Biology and Drug Discovery is involved in the discovery of chemical probes for methyllysine (Kme) readers since 2009. In silico approaches have been instrumental in all stages of this endeavor. For instance, pharmacophore- and structure-based virtual screening has lead to identification of small-molecule hits for L3MBTL1 [1], a malignant brain tumor (MBT) protein. Structure-based design was used throughout the probe development for L3MBTL3 [2], another MBT protein. Molecular simulations were helpful in understanding structural mechanisms of UHRF1, a ubiquitin ligase [3]. Current work includes hit/probe design for UHRF1 and identification of endogenous histone substrates for dual-domain readers. The talk will provide a brief overview of the past work and a discussion of new results.[1] Kireev et al, Identification of non-peptide malignant brain tumor (MBT) repeat antagonists by virtual screening of commercially available compounds. J Med Chem 2010, 53 (21), 7625-7631[2] James et al, Discovery of a chemical probe for the L3MBTL3 methyllysine reader domain. Nat Chem Biol 2013, 9 (3), 184-191[3] Rothbart et al, Multivalent histone engagement by the linked tandem Tudor and PHD domains of UHRF1 is required for the epigenetic inheritance of DNA methylation. Genes & Development 2013, 27 (11), 1288-1298

Computer-aided hit/probe discovery for methyllysine reader proteins

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.