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Evolutionary insights into the control of drug specificity

2010-11-10 , Fernandez, Ariel

We shall present on research endeavors focusing on controlling specificity in molecularly targeted anticancer therapy. A basic goal is to reduce toxic side effects by structure-based drug design exploiting our understanding of the evolutionary basis of specificity. Emphasis will be placed on engineering kinase inhibitors (KIs) with minimal clinical uncertainty. A radical innovation is on its way in terms of rationally redesigning KIs to reduce their toxicity. As it turns out, we can control specificity to an unprecedented degree and hence decisively contribute to test the limits of therapeutic efficacy. To support this claim, we start by noting that cross reactivities of KIs arise because of the structural similarity and amino acid conservation across evolutionarily related (paralog) kinases. Yet, while paralogs share a similar structure, they are "wrapped" differently. As we compare the microenvironments of intramolecular hydrogen bonds aligned across paralog structures we notice crucial differences: some hydrogen bonds are exposed to solvent in one kinase and shielded from water in another, or, rather, one hydrogen bond may be deficiently wrapped in one kinase but well wrapped in another. Taking into account such local differences, we are able to redesign KIs because deficiently wrapped hydrogen bonds -the so-called dehydrons - not only distinguish paralogs but are also inherently sticky. Hence, a new design strategy to achieve higher specificity emerges as we turn KIs into exogenous wrappers of dehydrons that are not conserved across structures of common ancestry. Such wrapping designs enable paralog discrimination and hence yield drugs capable of curbing side effects.