Wrapping as a Selectivity Filter for Molecular Targeted Therapy: Preliminary Evidence

Abstract

The conservation of structure across homolog proteins often diffuses the impact of drug-based inhibition by promoting alternative protein–ligand associations that may ultimately lead to toxic 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. This is because the clinically relevant targets, the kinases, evolved from each other and hence share an uncanny structural resemblance. However, as shown in the previous chapter, the sticky wrapping defects or dehydrons are typically not conserved across proteins of common ancestry, making them valuable a priori targets to enhance specificity. Thus, nonconserved packing defects may be utilized as selectivity switches across homolog targets. This chapter explores this paradigmatic concept and its ramifications for the rational design of drugs with controlled specificity.