Binding response: a descriptor for selecting ligand binding site on protein surfaces

Area of Science:

• Computational chemistry
• Structural biology
• Drug discovery

Background:

• Identifying protein binding sites is crucial for developing inhibitors targeting protein-ligand or protein-protein interactions.
• Virtual database screening relies heavily on accurate binding site identification for effective inhibitor selection.

Purpose of the Study:

• To introduce a novel descriptor, 'binding response', for quantitatively evaluating putative protein binding sites.
• To develop an automated approach for binding site identification to facilitate virtual screening and drug design.

Main Methods:

• Proposed a 'binding response' descriptor based on ligand-protein interaction energy and binding pose geometry.
• Utilized a test set of probe compounds to evaluate binding sites.
• Combined the binding response descriptor with sphere-based site identification and clustering methods.

Main Results:

• The binding response descriptor successfully identified experimental binding sites in 26 out of 29 known protein-ligand complexes.
• In the remaining three cases, the experimental binding site was ranked among the top three highest scoring sites.
• The integrated method provides an automated approach for binding site identification.

Conclusions:

• The novel binding response descriptor is effective for evaluating and identifying protein binding sites.
• The automated approach combining binding response with other methods enhances efficiency in drug discovery pipelines.
• This method supports both virtual database screening and de novo drug design strategies.