Protein structural dynamics in covalent drug design: insights from irreversible and reversible covalent inhibitors

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, and achieving an improved therapeutic effect, predominantly through sustained inhibitions. In this review, we focus on the impact of covalent bond formation on protein structural dynamics, such as the generation/trapping of cryptic pockets, and how these phenomena may be leveraged in orthosteric and allosteric drug design. 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. Herein, we explore selected case studies that examine the mechanistic consequences of protein-drug conjugations, recommending a more dynamic structural perspective in rational drug development.