Molecular similarity analysis uncovers heterogeneous structure-activity relationships and variable activity...

Area of Science:

• Biochemistry
• Structural Biology
• Medicinal Chemistry

Background:

• Understanding structure-activity relationships (SARs) is crucial for drug discovery.
• Enzyme inhibitor design often relies on correlating structural similarity with biological potency.
• Existing models struggle to explain inconsistencies in SARs across different enzyme targets.

Purpose of the Study:

• To systematically compare X-ray structures of inhibitor complexes for four enzymes.
• To correlate two- and three-dimensional (2D and 3D) inhibitor similarity with their potency.
• To uncover systematic relationships between molecular similarity and inhibitory activity.

Main Methods:

• Comparative analysis of X-ray crystallographic data for enzyme-inhibitor complexes.
• Quantitative assessment of 2D and 3D molecular similarity among inhibitors.
• Correlation analysis between structural similarity metrics and enzyme inhibition potency.

Main Results:

• Unexpected systematic relationships were found between molecular similarity and inhibitor potency.
• Structurally diverse ligands with similar activity can be identified even in constrained active sites.
• The chemical nature of ligands is as important as active site features for SARs.

Conclusions:

• Findings explain the coexistence of seemingly inconsistent SARs across different enzyme targets.
• Implications for compound screening and optimization in drug discovery.
• Enhanced understanding of target-specific SARs and their inherent variability.