Increasing the efficiency of ligands for FK506-binding protein 51 by conformational control

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Drug Discovery

Background:

• Designing effective ligands for challenging protein targets like FKBP51 is crucial in drug discovery.
• FKBP51 is an important target, but its open binding site presents significant design challenges.
• Understanding ligand conformational energy is key to improving binding affinity and drug-like properties.

Purpose of the Study:

• To design and synthesize novel bicyclic sulfonamides as potential ligands for FKBP51.
• To investigate the role of conformational preorganization and energy in ligand binding to FKBP51.
• To develop the first lead-like and functionally active ligand for FKBP51.

Main Methods:

• Design and synthesis of two new classes of bicyclic sulfonamides ([4.3.1] and [3.3.1] scaffolds) and monocyclic analogues.
• Affinity determination through binding assays.
• Cocrystallization of ligands with FKBP51 and atomic resolution structural analysis.
• Thermodynamic analysis of ligand binding (enthalpy and entropy contributions).

Main Results:

• The [4.3.1] bicyclic scaffold demonstrated consistently higher binding affinity compared to [3.3.1] or monocyclic scaffolds.
• Binding of the rigid [4.3.1] scaffold was enthalpy-driven and entropically disfavored, suggesting conformational preorganization.
• Cocrystal structures revealed an unusual hydrogen bond interaction involving the sulfonamide nitrogen and Tyr(113), mimicking the FKBP transition state.
• The first lead-like, functionally active ligand for FKBP51 was successfully developed.

Conclusions:

• Conformational control of ligands, particularly through rigid scaffolds like [4.3.1], can significantly enhance binding affinity for challenging targets like FKBP51.
• The identified unusual hydrogen bond interaction provides valuable insights into the FKBP51 binding mechanism.
• This study demonstrates a successful strategy for designing atom-efficient ligands for FKBP51 by optimizing conformational properties.