a theoretical entropy score as a single value to express inhibitor selectivity熵理论分数作为一个单一的价值表达抑制剂选择性.pdfVIP

Uitdehaag and Zaman BMC Bioinformatics 2011, 12:94 /1471-2105/12/94 RESEARCH ARTICLE Open Access A theoretical entropy score as a single value to express inhibitor selectivity * Joost CM Uitdehaag and Guido JR Zaman Abstract Background: Designing maximally selective ligands that act on individual targets is the dominant paradigm in drug discovery. Poor selectivity can underlie toxicity and side effects in the clinic, and for this reason compound selectivity is increasingly monitored from very early on in the drug discovery process. To make sense of large amounts of profiling data, and to determine when a compound is sufficiently selective, there is a need for a proper quantitative measure of selectivity. Results: Here we propose a new theoretical entropy score that can be calculated from a set of IC50 data. In contrast to previous measures such as the ‘selectivity score’, Gini score, or partition index, the entropy score is non- arbitary, fully exploits IC50 data, and is not dependent on a reference enzyme. In addition, the entropy score gives the most robust values with data from different sources, because it is less sensitive to errors. We apply the new score to kinase and nuclear receptor profiling data, and to high-throughput screening data. In addition, through analyzing profiles of clinical compounds, we show quantitatively that a more selective kinase inhibitor is not necessarily more drug-like. Conclusions: For quantifying selectivity from panel profiling, a theoretical entropy score is the best method. It is valuable for studying the molecular mechanisms of selectivity, and to steer compound progression in drug discovery programs. Background allow qualitative comparison of a limited set of c