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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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Distribution of hydrogen bonding penalties for: A) the binding modes in crystal structures of the 100 kinase complexes; B) poses with the most favorable calculated binding energies of the 138 molecules used in binding free energy calibration; C) all poses of the 138 molecules.
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pone-0019923-g002: Distribution of hydrogen bonding penalties for: A) the binding modes in crystal structures of the 100 kinase complexes; B) poses with the most favorable calculated binding energies of the 138 molecules used in binding free energy calibration; C) all poses of the 138 molecules.

Mentions: To check the distribution of HBP values in crystal structures, 100 kinase-ligand complexes are investigated. In this data set, all the small molecule inhibitors have molecular weights from 200 to 700 g/mol and number of donors or acceptors from 2 to 11 (File S2). The HBP has been calculated for each of them and the values are in general small, with 62% smaller than 1 and 36% and 2% in the range from 1 to 2 and 2.0 to 2.1, respectively (Figure 2 and File S2). It has also been observed that larger HBPs appear in some X-ray structures, e.g., the structures of PDB code 3KVX and 1JSV, and the large values actually originate from poor fitting of small molecules to the density, a common problem in crystallography [40] which can be manifested by clash of atoms.


Hydrogen bonding penalty upon ligand binding.

Zhao H, Huang D - PLoS ONE (2011)

Distribution of hydrogen bonding penalties for: A) the binding modes in crystal structures of the 100 kinase complexes; B) poses with the most favorable calculated binding energies of the 138 molecules used in binding free energy calibration; C) all poses of the 138 molecules.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0019923-g002: Distribution of hydrogen bonding penalties for: A) the binding modes in crystal structures of the 100 kinase complexes; B) poses with the most favorable calculated binding energies of the 138 molecules used in binding free energy calibration; C) all poses of the 138 molecules.
Mentions: To check the distribution of HBP values in crystal structures, 100 kinase-ligand complexes are investigated. In this data set, all the small molecule inhibitors have molecular weights from 200 to 700 g/mol and number of donors or acceptors from 2 to 11 (File S2). The HBP has been calculated for each of them and the values are in general small, with 62% smaller than 1 and 36% and 2% in the range from 1 to 2 and 2.0 to 2.1, respectively (Figure 2 and File S2). It has also been observed that larger HBPs appear in some X-ray structures, e.g., the structures of PDB code 3KVX and 1JSV, and the large values actually originate from poor fitting of small molecules to the density, a common problem in crystallography [40] which can be manifested by clash of atoms.

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