[Rational fragment-design method based on a thermodynamic analysis].

Area of Science:

• Biochemistry and Molecular Biology
• Pharmacology and Pharmaceutical Sciences

Context:

• Thermodynamic analysis provides insights into ligand-target interactions, crucial for drug discovery.
• Optimizing binding enthalpy is challenging but desirable for selecting effective drug candidates.
• The anti-ciguatoxin antibody 10C9 features a large antigen-binding pocket recognizing ciguatoxin via favorable enthalpy.

Purpose:

• To evaluate the utility of enthalpy change as a primary criterion in ligand-design for drug screening.
• To screen a chemical library using the anti-ciguatoxin antibody 10C9 as a model system.
• To identify compounds with favorable binding enthalpy to the 10C9 antibody.

Summary:

• Three compounds exhibited favorable binding enthalpy with the 10C9 antibody's antigen-binding pocket.
• These identified compounds share structural similarities with ciguatoxin, including cyclic structures and hydroxyl groups.
• The antibody selectively recognized these features, demonstrating enthalpy's role in specificity.

Impact:

• Enthalpy change serves as an effective index for rational ligand-design and drug screening.
• This approach can accelerate the identification of high-affinity drug candidates.
• The findings support prioritizing favorable binding enthalpy in early-stage drug development.