Purposely engineered drug-target mismatches for entropy-based drug optimization

Abstract

Proteins are dynamic objects, often undergoing significant structural change and reducing their conformational possibilities upon binding to a ligand. Thus, unless dynamic information is incorporated, structure-based drug design becomes of limited applicability. Even within a dynamic approach, a rarely visited scenario arises as proteins increase their entropy content upon binding by locally enhancing conformational exploration in the complex. We argue that this binding mode is of primary importance in drug development, since it allows for drugs that are not optimized in the conventional way but feature mismatches with the target, suggesting a new class of molecular design based on entropy optimization. This possibility is illustrated in this opinion piece, which advocates the exploitation of dynamic information for drug design.