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EpiRoadmap: Integration of chemogenomics-based approaches for epigenetic targets
Bergner A, Sheppard D, Slater M.
Genome sequencing and progress in protein structure determination has led to a vast and rapidly growing amount of sequence data and 3D structural information that facilitate drug discovery research for many different target families. Addressing selectivity opportunities and risks across entire target families have increasingly become important at various stages of drug discovery projects, including hit finding, focused library design and lead optimization. Chemogenomics based approaches such as BioFocus’ kinase 2D Roadmap™ (1) and Thematic Analysis™ (2) have been successfully used over the past ten years in the design of the SoftFocus® libraries.
BioFocus has developed a new Java-based platform that integrates and enhances the ideas and concepts of previously derived Roadmap approaches. Using a model which dynamically represents all relevant data relations in an intuitive user interface, it enables the fast interactive setup of roadmap cartoons (logical maps) for any target family. Rapid browsing through selected members of a target family and target list handling are implemented as well as differential plots for comparing target and off-target binding sites or sub-sites. These can be configured using various metrics and graphical layout options. Advanced features include similarity searching and clustering for all residues or defined subsets of a drug binding site. Using the platform allows computational and medicinal chemists to quickly attain an overview of relevant characteristics of important targets of a target class, and to more efficiently drive drug discovery projects with cross-target challenges.
Epigenetics is ideal for such a toolkit as is offers an abundance of structural information localized into protein families or sub-families. The potential of the tool is demonstrated using the PKMT (protein lysine methyl-transferase) subfamily of HMTs (histone methyl transferase), an epigenetics target class.
(1) Harris and Stevens, DDT, 2006
(2) Crossley and Slater, Chemogenomics (Ed. E.Jacoby, Imperial College London Press), 2006, 85-108
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