Drug-Target Associations Inducing Protein Folding
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Structure-based drug design has met only modest success due mainly to two reasons: a) as shown in the previous chapter, pharmacologically relevant features are often enshrined in the epistructure, not in the structure itself; and b) the targettable features are often found in structurally floppy regions. In this chapter we shall focus on the latter aspect, first highlighting the inadequacy of standard rational design to deal with it. This is because structural adaptation upon ligand binding resulting in induced folding is usually very difficult to predict. Thus, dynamic information must be incorporated into rational drug design. The conformation of the protein chain in complex with the drug ligand often differs significantly from the conformation of the apo form of the protein, and the structural difference is often unpredictable. In fact, the induced folding problem is every bit as difficult as the protein folding problem, whose arduous solution required a combination of structural and epistructural approaches, as described in Chap. 3. Local conformational plasticity of the protein target is probably the main reason for the modest interest in rational drug design. Thus, floppy regions such as the activation loop or nucleotide-binding loop in a kinase are seldom targeted with small molecule inhibitors in spite of their value as selectivity filters. For example, the activation loop is the structural region that presents the largest amino acid variability within kinase families and thus its compositional uniqueness makes it an attractive target to control specificity. In this chapter we advocate for a strategy to target flexible regions, offering a way to control the induced folding and turn it into a selectivity-promoting feature. Drugs designed to wrap disordered regions in the target may be used to steer induced folding in specific controllable ways, i.e. by inducing the formation of specific dehydrons. The results surveyed in this chapter herald the paradigmatic concept of “wrapping drugs for structurally adaptable targets”. The wrapping-induced folding concept is illustrated by redesigning the anticancer drug imatinib in order to redirect its affinity towards a floppy region in JNK1, which constitutes an important target in the treatment of ovarian cancer. Thus, this chapter reveals that insights from epistructural physics become essential to incorporate conformational dynamics into the technological base of the drug design platforms.
KeywordsOvarian Cancer Chronic Myeloid Leukemia Activation Loop Packing Defect Rational Drug Design
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