Quantum Mechanics-Based Fast and Reliable Prediction of Binding Pose Structures.

Predicting the binding poses of docking with an accurate estimation of binding energies is highly important but very challenging in computational drug design. A quantum mechanics (QM) calculation-based docking approach considering multiple conformations and orientations of the ligand is introduced here to tackle the problem. This QM docking consists of three steps: generating an ensemble of binding poses with a conventional docking simulation, computing the binding energies with self-consistent charge density functional theory tightly binding with dispersion correction (DFTB-D) to selecting the 10 top binding modes, and optimizing the selected binding mode structures using the ONIOM(DFTB:PM7) technique to determine the binding poses. The ONIOM(DFTB-D:PM6) docking approach is tested on 121 ligand-receptor biocomplexes with the crystal structures obtained from the Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB). The result shows that the new method is highly satisfactory for the accurate prediction of the binding poses. The new docking method should be beneficial to structure-based drug design.

MDO: A Computational Protocol for Prediction of Flexible Enzyme-Ligand Binding Mode.

AIM: Developing a method for use in computer aided drug design Background: Predicting the structure of enzyme-ligand binding mode is essential for understanding the properties, functions, and mechanisms of the bio-complex, but is rather difficult due to the enormous sampling space involved. OBJECTIVE: Accurate prediction of enzyme-ligand binding mode conformation. METHOD: A new computational protocol, MDO, is proposed for finding the structure of ligand binding pose. MDO consists of sampling enzyme sidechain conformations via molecular dynamics simulation of enzyme-ligand system and clustering of the enzyme configurations, sampling ligand binding poses via molecular docking and clustering of the ligand conformations, and the optimal ligand binding pose prediction via geometry optimization and ranking by the ONIOM method. MDO is tested on 15 enzyme-ligand complexes with known accurate structures. RESULTS: The success rate of MDO predictions, with RMSD < 2 Å, is 67%, substantially higher than the 40% success rate of conventional methods. The MDO success rate can be increased to 83% if the ONIOM calculations are applied only for the starting poses with ligands inside the binding cavities. CONCLUSION: The MDO protocol provides high quality enzyme-ligand binding mode prediction with reasonable computational cost. The MDO protocol is recommended for use in the structure-based drug design.