An anchor-dependent molecular docking process for docking small flexible molecules into rigid protein receptors

Area of Science:

• Computational chemistry
• Molecular modeling
• Drug discovery

Background:

• Molecular docking is crucial for identifying drug candidates.
• Existing methods face challenges in accuracy and efficiency for flexible ligands.
• A need exists for robust methods to score and rank potential drug-receptor interactions.

Purpose of the Study:

• To introduce ADDock, a novel anchor-dependent molecular docking method.
• To evaluate ADDock's accuracy in predicting receptor-ligand complex structures.
• To assess ADDock's capability in differentiating active from inactive compounds.

Main Methods:

• ADDock utilizes anchor-based construction of ligand conformations.
• It employs an extended piecewise linear potential for scoring.
• The method systematically explores docking poses by varying anchors without translational motion.
• No energy minimization is required post-docking for scoring.

Main Results:

• ADDock achieved 91.3% accuracy across 92 diverse receptor-ligand complexes.
• The method demonstrated significant separation of steric interaction energies between active and inactive compounds.
• Computed steric interactions effectively distinguished compounds docked into the same receptor active sites.

Conclusions:

• ADDock provides a highly accurate and efficient molecular docking solution.
• The method's scoring reliably differentiates active from inactive compounds.
• ADDock shows promise for accelerating drug discovery and lead optimization.