Rationally designing specificity for the druggable oncokinome : A pharmacoinformatics analysis for molecular cancer therapy
Background and Motivation: Protein k inases, the quintessential signal transducers of the cell, are regarded as promising targets for drug-based cancer therapy.
However, due to a common evolutionary ancestry, human kinases are structurally very similar, and thus their targeted inhibition is often plagued with side effects that may even be life-threatening. These side effects result from uncontrolled drug cross reactivities, in turn arising from the structural similarity of the targets. Thus, rational design of kinase inhibitors remains a challenge partly because there is no clear delineation of the molecular/structural 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 rea ctivity. Thus, a core question in the informatics of drug design is what type of molecular similarity among targets promotes promiscu ity and what type of molecular difference governs specificity. This lecture provides answers the question for a sizable screened sample of the human pharmacokinome by introducing a "pharmacological distance " and comparing it to a structure-based distance between kinase targets.
Results: We show that drug design aimed at promoting pair wise interactions between ligand and kinase target actually fosters promiscuity because of the high conservation of the par tner groups on or around the ATP-binding site of the kinase. Alternatively, we focus on a structural marker, the wrapping, that measures dehydration propensities mostly localized on the loopy regions of kinases. Based on this marker, we construct a kinase classifier, the wrapping distance , that enables the accurate prediction of pharmacological differences. Our indicator is a microenvironmen tal 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.
The analysis is specialized to solve one concrete medical problem: How to redesign the powerful anticancer drug imatinib (Gleevec) to curb its carditoxicity , an unticipated side effect arising from imatinib cross reactivity . We shall report on promising in vitro and in vivo results in this regard.