Bioinformatics Advance Access originally published online on January 25, 2007
Bioinformatics 2007 23(5):563-572; doi:10.1093/bioinformatics/btl666
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Molecular basis for specificity in the druggable kinome: sequence-based analysis
1Program in Applied Physics and Rice Quantum Institute, 2Department of Bioengineering, Rice University, Houston, TX 77005, USA and 3Department of Computer Science, The University of Chicago, Chicago, IL 60637, USA
*To whom correspondence should be addressed.
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Abstract |
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Motivation: Rational design of kinase inhibitors remains a challenge partly because there is no clear delineation of the molecular features that direct the pharmacological impact towards clinically relevant targets. Standard factors governing ligand affinity, such as potential for intermolecular hydrophobic interactions or for intermolecular hydrogen bonding do not provide good markers to assess cross reactivity. Thus, a core question in the informatics of drug design is what type of molecular similarity among targets promotes promiscuity and what type of molecular difference governs specificity. This work answers the question for a sizable screened sample of the human pharmacokinome including targets with unreported structure.
Results: We show that drug design aimed at promoting pairwise interactions between ligand and kinase target actually fosters promiscuity because of the high conservation of the partner groups on or around the ATP-binding site of the kinase. Alternatively, we focus on a structural marker that may be reliably determined from sequence and measures dehydration propensities mostly localized on the loopy regions of kinases. Based on this marker, we construct a sequence-based kinase classifier that enables the accurate prediction of pharmacological differences. Our indicator is a microenvironmental descriptor that quantifies the propensity for water exclusion around preformed polar pairs. The results suggest that targeting polar dehydration patterns heralds a new generation of drugs that enable a tighter control of specificity than designs aimed at promoting ligand–kinase pairwise interactions.
Availability: The predictor of polar hot spots for dehydration propensity, or solvent-accessible hydrogen bonds in soluble proteins, named YAPView, may be freely downloaded from the University of Chicago website http://protlib.uchicago.edu/dloads.html
Contact: arifer{at}rice.edu, ariel{at}uchicago.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
Received on October 9, 2006; revised on December 8, 2006; accepted on December 28, 2006
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