Impact of Irreversible and Reversible Covalent Inhibitors on Structural Dynamics of Target Proteins

Abstract

Proteins form complex networks critical to various biological processes; many become involved in disease-related pathologies -only a subset of these proteins are considered to be druggable by conventional, non-covalent small-molecule therapeutics. Covalent drugs, which encompass irreversible inhibitors and reversible covalent inhibitors, are small-molecule modalities that chemically conjugate with their therapeutic targets and have emerged as a strategy to more effectively target these proteins, with structure-based approaches guiding their design. It is known that ligand binding can initiate conformational rearrangements in proteins, whether localized or extensive, and can have important biological implications.However, in many cases, the structural dynamics induced by chemical conjugation with the drug are overlooked. It is important to appreciate protein conformational transitions post-interaction, which can range from subtle backbone or side chain shifts to more large-scale changes such as domain movements or local unfolding as well as the creation of cryptic pockets. Insights from these studies may then be harnessed into drug optimization strategies. Further, while irrreversible inhibitors result in longer residence times with permanent changes of target proteins that will require protein re-synthesis, reversible covalent inhibitors enjoy the benefit of samplng different adducts, wherein one particular conjugate may be favoured through stabilizing structural reogranizations; this may prove significant when a protein presents multiple nucleophilic residues, and selectivity is a concern. This review emphasizes the need to integrate knowledge on protein structural alterations into covalent drug design and explores selected case studies that examine the mechanistic consequences of drug-protein interactions, recommending a more dynamic structural perspective in rational drug development.