Quantitative Structure-Activity Relationships for Human Galectin-3 Inhibitors: Insights from Quantum Chemical...

Area of Science:

• Computational chemistry
• Medicinal chemistry
• Molecular modeling

Background:

• Human galectin-3 (hGal-3) is a protein target implicated in various diseases, including fibrosis.
• Several hGal-3 inhibitors have been identified, but optimizing their binding affinity requires a deeper understanding of structure-activity relationships.

Purpose of the Study:

• To investigate the quantitative structure-activity relationships (QSAR) influencing hGal-3 inhibitor binding affinity.
• To identify key quantum chemical interactions and specific hGal-3 residues contributing to binding affinity.
• To propose design guidelines for developing high-affinity hGal-3 inhibitors.

Main Methods:

• Utilized fragment molecular orbital (FMO) calculations to derive electrostatic, charge transfer (CT+mix), exchange, and dispersion interaction energy terms for 21 hGal-3 inhibitors.
• Performed quantitative structure-activity relationship (QSAR) analysis to correlate interaction energies with binding affinity.
• Decomposed interaction terms to analyze contributions from specific hGal-3 residues (R144, N160, E184, R186).

Main Results:

• Binding affinity was primarily explained by charge transfer (CT+mix) and dispersion (DI) interactions.
• Key CT+mix interactions involved residues R144, N160, E184, and R186, with charge transfer from E184 stabilizing the interaction.
• Significant DI interactions were observed with R144 and R186, involving pi-stacking and CH-pi interactions.

Conclusions:

• The FMO-based QSAR approach provides insights into quantum chemical interactions governing hGal-3 binding affinity.
• Design strategies should focus on facilitating charge transfer from E184 and enhancing dispersion interactions through shape complementarity near R144 and R186.
• This study offers a novel perspective for the rational design of potent hGal-3 inhibitors.