Are there physicochemical differences between allosteric and competitive ligands?

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Pharmacology

Background:

• Previous research suggested allosteric compounds possess distinct physicochemical properties (smaller, more rigid, hydrophobic, drug-like) compared to non-allosteric ones.
• Concerns exist that prior findings may be skewed by data biases, particularly from protein targets with abundant associated data.

Purpose of the Study:

• To rigorously assess the robustness of previously reported physicochemical differences between allosteric and non-allosteric ligands.
• To investigate potential data biases and their impact on established structure-activity relationships in allosteric drug discovery.

Main Methods:

• Utilized the Allosteric Database (ASD v3.0) and ChEMBL v20 to compile large datasets of allosteric (70,219) and competitive (9,511) ligands.
• Computed physically relevant compound descriptors to analyze chemical property variations.
• Implemented data redundancy removal and normalization strategies across diverse protein targets and ligand sets.

Main Results:

• Confirmed that allosteric ligands exhibit increased aromaticity and rigidity compared to competitive ligands.
• Did not find significant differences in hydrophobicity or drug-likeness between allosteric and competitive ligand sets after normalization.
• Observed that these findings remained consistent across various data normalization schemes.

Conclusions:

• The previously reported increased hydrophobicity and drug-likeness of allosteric compounds are not robust findings when accounting for data bias.
• Allosteric ligands are characterized by higher aromaticity and rigidity, properties that are consistently observed even with normalized datasets.
• This study refines the understanding of allosteric ligand physicochemical profiles, crucial for targeted drug design and discovery.