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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.

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Identified EphB4 inhibitors by high throughput docking.a All IC50 values are means of two to four dose-response measurements.
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pone-0019923-g005: Identified EphB4 inhibitors by high throughput docking.a All IC50 values are means of two to four dose-response measurements.

Mentions: Notably, 4 of the 9 tested compounds show inhibitory activity at micro-molar to high nano-molar range, with the most active compound showing IC50 at 300 nM (Figure 5). Interestingly, the two compound also show a high ligand efficiency [42] of −0.35 kcal/mol per non-hydrogen atom. The predicted binding mode of compound 3 (Figure 6) is further confirmed by the preliminary X-ray crystallography (J. Dong, unpublished results).


Hydrogen bonding penalty upon ligand binding.

Zhao H, Huang D - PLoS ONE (2011)

Identified EphB4 inhibitors by high throughput docking.a All IC50 values are means of two to four dose-response measurements.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0019923-g005: Identified EphB4 inhibitors by high throughput docking.a All IC50 values are means of two to four dose-response measurements.
Mentions: Notably, 4 of the 9 tested compounds show inhibitory activity at micro-molar to high nano-molar range, with the most active compound showing IC50 at 300 nM (Figure 5). Interestingly, the two compound also show a high ligand efficiency [42] of −0.35 kcal/mol per non-hydrogen atom. The predicted binding mode of compound 3 (Figure 6) is further confirmed by the preliminary X-ray crystallography (J. Dong, unpublished results).

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