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Hydrogen bonding penalty upon ligand binding.

Zhao H, Huang D - PLoS ONE (2011)

Bottom Line: A new model integrated with hydrogen bonding penalty for free energy calculation gives a root mean square error of 0.7 kcal/mol on 74 inhibitors in the training set and of 1.1 kcal/mol on 64 inhibitors in the test set.Moreover, an application of hydrogen bonding penalty into a high throughput docking campaign for EphB4 inhibitors is presented, and remarkably, three novel scaffolds are discovered out of seven tested.The binding affinity and ligand efficiency of the most potent compound is about 300 nM and 0.35 kcal/mol per non-hydrogen atom, respectively.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Zurich, Zurich, Switzerland.

ABSTRACT
Ligand binding involves breakage of hydrogen bonds with water molecules and formation of new hydrogen bonds between protein and ligand. In this work, the change of hydrogen bonding energy in the binding process, namely hydrogen bonding penalty, is evaluated with a new method. The hydrogen bonding penalty can not only be used to filter unrealistic poses in docking, but also improve the accuracy of binding energy calculation. A new model integrated with hydrogen bonding penalty for free energy calculation gives a root mean square error of 0.7 kcal/mol on 74 inhibitors in the training set and of 1.1 kcal/mol on 64 inhibitors in the test set. Moreover, an application of hydrogen bonding penalty into a high throughput docking campaign for EphB4 inhibitors is presented, and remarkably, three novel scaffolds are discovered out of seven tested. The binding affinity and ligand efficiency of the most potent compound is about 300 nM and 0.35 kcal/mol per non-hydrogen atom, respectively.

Show MeSH
Schematic picture of the high throughput docking approach.HB stands for hydrogen bond. Met696 and Glu694 are the two key residues of the hinge loop (see also Figure 6).
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pone-0019923-g004: Schematic picture of the high throughput docking approach.HB stands for hydrogen bond. Met696 and Glu694 are the two key residues of the hinge loop (see also Figure 6).

Mentions: The focused library was docked by AutoDock 4 and about 1 million poses were generated by clustering with a RMSD cutoff of 1.0 Å. The cluster representatives which do not form a hydrogen bond to NH of Met696 were further filtered out. The HBP (≤2) was then used to remove unrealistic poses (about 40%). The remaining poses were further ranked by the predicted binding energy, and the top about 30% compounds (22,517) with calculated binding energy smaller than −6 kcal/mol (∼50 µM) were kept. Among them, 1381 compounds forming a hydrogen bond to Glu694 were selected and can be classified into 80 structural scaffolds. Finally, 7 scaffolds (9 compounds) of them were purchased for experimental measurements based on visual inspection of the binding modes, commercial availability and structural novelty. The procedures used in the virtual screening are shown in Figure 4. Comparison of the performances between the proposed and AutoDock 4 scoring function is shown in Figure S6.


Hydrogen bonding penalty upon ligand binding.

Zhao H, Huang D - PLoS ONE (2011)

Schematic picture of the high throughput docking approach.HB stands for hydrogen bond. Met696 and Glu694 are the two key residues of the hinge loop (see also Figure 6).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3117785&req=5

pone-0019923-g004: Schematic picture of the high throughput docking approach.HB stands for hydrogen bond. Met696 and Glu694 are the two key residues of the hinge loop (see also Figure 6).
Mentions: The focused library was docked by AutoDock 4 and about 1 million poses were generated by clustering with a RMSD cutoff of 1.0 Å. The cluster representatives which do not form a hydrogen bond to NH of Met696 were further filtered out. The HBP (≤2) was then used to remove unrealistic poses (about 40%). The remaining poses were further ranked by the predicted binding energy, and the top about 30% compounds (22,517) with calculated binding energy smaller than −6 kcal/mol (∼50 µM) were kept. Among them, 1381 compounds forming a hydrogen bond to Glu694 were selected and can be classified into 80 structural scaffolds. Finally, 7 scaffolds (9 compounds) of them were purchased for experimental measurements based on visual inspection of the binding modes, commercial availability and structural novelty. The procedures used in the virtual screening are shown in Figure 4. Comparison of the performances between the proposed and AutoDock 4 scoring function is shown in Figure S6.

Bottom Line: A new model integrated with hydrogen bonding penalty for free energy calculation gives a root mean square error of 0.7 kcal/mol on 74 inhibitors in the training set and of 1.1 kcal/mol on 64 inhibitors in the test set.Moreover, an application of hydrogen bonding penalty into a high throughput docking campaign for EphB4 inhibitors is presented, and remarkably, three novel scaffolds are discovered out of seven tested.The binding affinity and ligand efficiency of the most potent compound is about 300 nM and 0.35 kcal/mol per non-hydrogen atom, respectively.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Zurich, Zurich, Switzerland.

ABSTRACT
Ligand binding involves breakage of hydrogen bonds with water molecules and formation of new hydrogen bonds between protein and ligand. In this work, the change of hydrogen bonding energy in the binding process, namely hydrogen bonding penalty, is evaluated with a new method. The hydrogen bonding penalty can not only be used to filter unrealistic poses in docking, but also improve the accuracy of binding energy calculation. A new model integrated with hydrogen bonding penalty for free energy calculation gives a root mean square error of 0.7 kcal/mol on 74 inhibitors in the training set and of 1.1 kcal/mol on 64 inhibitors in the test set. Moreover, an application of hydrogen bonding penalty into a high throughput docking campaign for EphB4 inhibitors is presented, and remarkably, three novel scaffolds are discovered out of seven tested. The binding affinity and ligand efficiency of the most potent compound is about 300 nM and 0.35 kcal/mol per non-hydrogen atom, respectively.

Show MeSH