Is It Reliable to Take the Molecular Docking Top Scoring Position as the Best Solution without Considering Available...

Area of Science:

• Computational Chemistry
• Structural Biology
• Drug Discovery

Background:

• Molecular docking is a key computational technique for understanding drug-target interactions.
• Accurately predicting ligand binding poses is crucial for drug design.
• The energy score is commonly used to select the best docking pose, but its reliability is debated.

Purpose of the Study:

• To evaluate the reliability of docking energy scores in reproducing experimental binding poses.
• To compare the performance of rigid-target docking methods in self-docking and cross-docking scenarios.
• To determine if the best energy score is a dependable criterion for selecting the optimal ligand pose.

Main Methods:

• Evaluated several rigid-target docking methods on a standardized dataset.
• Performed self-docking (ligand in its own receptor) and cross-docking (ligand in a receptor with a different ligand).
• Utilized root-mean square deviation (RMSD) to quantify the difference between predicted and crystallographic poses.

Main Results:

• Docking score functions can predict crystallographic binding orientations.
• The top-ranked pose by energy score does not always match the experimental binding orientation.
• This discrepancy was observed in self-docking and was more pronounced in cross-docking.

Conclusions:

• The best energy score is not a consistently reliable criterion for selecting the best docking solution in typical applications.
• Additional structural criteria, beyond energy scoring, are recommended for accurate pose selection.
• Improving pose selection methods is vital for the predictive power of molecular docking in drug discovery.