EntropySelect™

EntropySelect™ is the bioinformatics and chemical biology toolbox of NTRC that enables the identification of novel starting points for drug discovery. From our database of kinase inhibitor profiles and our selectivity entropy method we define selective starting points for new drug discovery. We generate X-ray protein structures to optimize initial hits into drug leads.

• Do you have an interesting biological target and are you looking for a selective tool compound?
• Do you have a validated target and need chemical matter to start a drug discovery project?

Introduction to EntropySelect™

Selectivity entropy is a way to mathematically describe the selectivity of a compound in one single value. It is a descriptor of the properties of a compound, similar to affinity or Kd value. Whereas affinity expresses the strength of an interaction of a compound with one single target protein, selectivity entropy captures its interaction with a broad panel of different proteins. Such a panel can, for instance, be a kinase assay profiling panel. If you are interested in drug discovery on a new interesting biological concept, we apply EntropySelect™ to identify a first chemical starting point that is both selective and potent and use this for further biological target validation or drug discovery. Through its focus on selectivity, EntropySelect™ decreases the chance of side-effects due to unwanted cross-reactivity of compounds

Theory behind Selectivity Entropy

The method of Selectivity Entropy assumes a theoretical mixture of all targets in a pharmacological test panel. The prototypic example of such a test panel is all kinases in a kinome profiling study. Selectivity entropy uses IC50, EC50 or Kd values from the profiling study. It can also use % inhibition data at a single compound concentration.The law of Boltzmann is used to calculate the theoretical distribution of the compound across the different targets. The broadness of the distribution is characterized by an entropy as defined in Gibb’s formula. Selectivity entropy thus condenses panel profiling data into a single value that provides a quantitative measure of the selectivity of a compound.

EntropySelect™ in practice

NTRC has an activity database with more than 1800 kinome profiles that we use to identify selective starting points for new kinase targets. Compounds are synthesized and optimized using 3D modeling and protein crystallography. EntropySelect™ can be used to identify tool compounds for target validation and new chemotypes for drug discovery. In combination with our medicinal chemistry capabilities, molecular profiling and protein sciences expertise, EntropySelect™ enables us to deliver new chemical starting points for kinase drug discovery within a shorter timeline than traditional approaches.

For more information please send an e-mail to info@ntrc.nl

Literature

Uitdehaag JCM, Zaman GJR, BMC Bioinformatics (2011), 12, 94
Uitdehaag JC, et al, Br J Pharmacol. (2012), 166(3), 858-76.