Conformational Plasticity and Binding Affinity Enhancement Controlled by Linker Derivatization in Macrocycles

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Drug Discovery

Background:

• Nature utilizes macrocycles for cell-permeable bioactive molecules.
• Synthetic macrocycles are emerging as drug modalities for challenging protein targets.
• Understanding macrocycle conformational flexibility is crucial for rational design.

Purpose of the Study:

• To investigate the conformational plasticity of synthetic macrocycles.
• To explore how linker modifications impact macrocycle conformation and binding.
• To develop novel ligands for the FK506-binding protein 51.

Main Methods:

• Synthesis of modified macrocycles.
• Structural analysis of macrocycle-protein complexes.
• Affinity and physicochemical property assessment.

Main Results:

• Medium-sized macrocycles exhibit significant conformational plasticity, even when protein-bound.
• Linker modifications can shift the conformational ensemble, creating distinct binding scaffolds.
• Novel ligands with enhanced affinity and improved properties were identified for FKBP51.

Conclusions:

• Macrocyclization provides a versatile platform beyond simple conformational constraint.
• Linker modifications enable access to diverse binding modes and drug-like properties.
• This approach facilitates the discovery of macrocyclic drugs for complex targets like FKBP51.