The Biomolecular Interface as a Selectivity Filter for Drug-Based Targeted Therapy
The conservation of structure across homologous proteins introduces a hurdle in the quest to control specificity in molecular targeted therapy. Accordingly, this chapter and the ones that follow argue for an epistructure-based rather than a structure-based approach to drug design, noting that the filter for drug specificity is subsumed in the aqueous interface of the target protein and not in the protein structure itself. Because rational drug design remains essentially structure-based, the impact of drug-based inhibition often spreads to several members of a protein family sharing a common fold. This promiscuity leads to undesirable target-drug associations that may ultimately cause health-threatening or pernicious side effects. This problem becomes particularly acute when attempting to interfere with signaling pathways involved in cell fate and cell proliferation, the type of molecular intervention often exploited in molecular anticancer therapy. In this context, the therapeutically relevant targets are the kinases, signal transducers that evolved from each other and hence share an uncanny structural similarity. However, as previously shown, the sticky packing defects named dehydrons are often not conserved across proteins of common ancestry, making them valuable a priori targets to enhance specificity. Non-conserved dehydrons may be utilized as selectivity switches across homologous targets. This chapter explores this paradigmatic concept and its ramifications for the rational design of drugs with controlled specificity. The main rationale for this design strategy can be summarized as follows: If the packing defect is an enabler and stimulator of catalytic function (Chap. 7), then its removal through intermolecular wrapping upon drug-target association should impair the function of the targeted protein and do so with high specificity, which is precisely the goal of molecular targeted therapy. This rationale thus heralds the paradigmatic concept of “drug as dehydron wrapper” described and explored in this chapter.
KeywordsDrug Design Structural Alignment Activation Loop Selectivity Filter Packing Defect
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