Chemical adaptation: bridging synthetic chemistry with drug development

Structure-based drug design (SBDD) has profoundly advanced the rational development of small molecule therapeutics by enabling the systematic optimization of drug-target interactions. A variety of molecular recognition models provide conceptual frameworks for understanding these interactions, thereby facilitating improvements in binding affinity, target selectivity, and pharmacokinetic profiles-key determinants of clinical success. To better emphasize the chemical nature of these interactions and to enhance the accessibility of rational drug design concepts for the synthetic chemistry community, we introduce chemical adaptation as a complementary framework to SBDD, offering an alternative, chemistry-oriented perspective for interpreting ligand-target interactions. This concept highlights deliberate, chemically driven strategies for optimizing ligand binding and improving drug-like characteristics. We classify chemical adaptation into four principal categories: ligand template adaptation (aligning the ligand's core structure with the topology of the target binding pocket), scaffold steric adaptation (refining the spatial orientation and steric complementarity of the molecular scaffold), functional group adaptation (modulating non-covalent interactions and physicochemical properties), and proximity-induced reactivity adaptation (leveraging covalent reactivity to strengthen target engagement). Collectively, these strategies underscore the necessity of precisely tailoring ligand structures to achieve optimal drug-like properties and offer a versatile, chemistry-centered framework applicable to the design of small molecule drugs across a broad spectrum of biological targets and therapeutic modalities.