The size matters? A computational tool to design bivalent ligands

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Structural Biology

Background:

• Bivalent ligands are crucial for targeting protein-protein interactions, such as G protein-coupled receptor (GPCR) dimers and proteolysis targeting chimeras (PROTACs).
• These ligands feature two pharmacophores connected by a spacer, enabling simultaneous binding to distinct sites.

Purpose of the Study:

• To introduce a novel molecular modeling tool for designing and prioritizing bivalent ligands.
• To optimize linker length and placement for enhanced binding affinity and specificity.

Main Methods:

• The tool calculates the shortest pathway along the receptor's van der Waals surface to connect pharmacophore units.
• It employs scoring functions to evaluate and rank potential bivalent ligand designs.
• Analysis included known GPCR dimers, PROTACs, and antibody/antigen systems.

Main Results:

• The tool accurately predicted optimal linker lengths for various bivalent ligand systems.
• It successfully recapitulated previously reported successful bivalent ligand designs.
• For GPCR dimers, findings suggest potential binding to allosteric sites in addition to orthosteric sites.

Conclusions:

• The developed molecular modeling tool provides an efficient method for designing novel bivalent ligands.
• It aids in understanding ligand-receptor interactions, particularly for complex systems like GPCR dimers.
• The tool is freely accessible, promoting further research in bivalent ligand design.