Understanding and exploiting druggable conformations

Proteins adopt a variety of conformations to exert their biological function. This conformational flexibility implies the variation of the size and availability of binding sites, which paves the way for designing drugs with distinct affinity and selectivity.

Drug-target interactions often entail conformational rearrangements in one or both of the binding partners. Several mechanisms explain this: compounds capable of inducing conformational changes in the target, compounds that bind exclusively to specific conformations or molecules that form covalent complexes.

Assessing the parameters that define the steps of the binding mechanism is pivotal for the successful optimization of promising compounds.

Applications

• Obtain structural information in the absence of crystal structures.
• Enhanced decision-making: Ideal hit-to-lead and lead optimization tool to exploit protein flexibility.
• Improve optimization through detailed mechanistic profiling: Explore the mechanisms behind simple reversible compounds, those binding to specific conformations or eliciting conformational changes in the target, and reversible or irreversible covalent inhibitors.
• Understand PK/PD disconnects: Kinetic profiling often bridges the gap between PK/PD prediction and observation.
• Build better models: PK/PD models that integrate kinetics better predict target engagement, drug dose and treatment schedule.