Protein pocket and ligand shape comparison and its application in virtual screening

Area of Science:

• Computational chemistry
• Structural biology
• Drug discovery

Background:

• Molecular recognition is crucial for drug discovery and design.
• Shape and physicochemical complementarity drive complex formation between binding partners.
• Understanding the role of shape in this process is essential.

Purpose of the Study:

• To analyze the impact of molecular shape on protein-ligand complex formation.
• To investigate the relationship between binding pocket/ligand shape and bioactivity/binding efficiency.
• To evaluate shape and size parameters in a virtual screening context.

Main Methods:

• Representing protein binding pockets and ligands using normalized principal moments of inertia ratios (NPRs).
• Analyzing shape complementarity through pairwise shape distances, center-of-mass distances, and principal axis angle deviations.
• Assessing binding pocket parameters' relation to bioactivity and binding efficiency.
• Evaluating shape and size parameters in virtual screening on four targets.

Main Results:

• Protein pockets and ligands tend to avoid spherical shapes, which are more common in small, unoccupied pockets.
• On average, ligands fill about one-third of the binding pocket volume with 50% subpocket coverage.
• Shape complementarity is characterized by low shape distances in NPR space, short center-of-mass distances, and aligned principal axes.
• Binding pocket and ligand shape parameters show varying performance in virtual screening.

Conclusions:

• Molecular shape is a critical determinant in molecular recognition and drug design.
• The study provides quantitative measures for shape complementarity.
• The findings have implications for improving virtual screening strategies and drug design by considering shape parameters.