Binding selectivity studies of phosphoinositide 3-kinases using free energy calculations

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Abstract

Phosphoinositide 3-kinases (PI3Ks) and their phosphatidylinositol 3,4,5-triphosphate (PIP3) products regulate a variety of cellular processes. Of these, PI3Kα is an attractive target for anticancer drug design. Mutations in the PI3Kα kinase domain alter the mobility of the activation loop resulting in gain of function. We employed molecular dynamics (MD) simulations-based energetic analysis using molecular mechanics/generalized born surface area (MM/GBSA) for PI3Kα and -γ. MD simulations were carried out for PI3K models based on the RESP (restrained electrostatic potential) and quantum mechanics (QM)-polarized ligand docking (QPLD)-derived partial charges. Computational alanine scanning was also used to evaluate the contributions of key binding residues to ligand binding. Our results show that both RESP and QPLD charge models of PI3Kα and PI3Kγ provide similar performance in MD simulations. For example, the predicted RESP and QPLD free energies of -9.5 and -9.3 kcal/mol for LY294002 binding to PI3Kγ and -10.9 and -11.7 kcal/mol for wortmannin binding to PI3Kα are in good agreement with experimental values. A significant loss in binding free energy was observed when hydrophobic residues were mutated to alanine, suggesting that specific hydrophobic interactions are important to optimal ligand binding. MM/GBSA calculations suggested that residues Ser774, Gln859, and Ile932 of PI3Kα might be used to design H1047R mutant-specific ligands, whereas Lys890 of PI3Kγ can be used for ligand design targeting PI3Kγ.

Original languageEnglish (US)
Pages (from-to)3213-3224
Number of pages12
JournalJournal of Chemical Information and Modeling
Volume52
Issue number12
DOIs
StatePublished - Dec 21 2012

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Phosphatidylinositols
mechanic
Free energy
Phosphotransferases
Ligands
energy
simulation
Molecular dynamics
Electrostatics
Molecular mechanics
activation
Computer simulation
drug
Alanine
interaction
Quantum theory
performance
Values
1-Phosphatidylinositol 4-Kinase
Chemical activation

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences

Cite this

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title = "Binding selectivity studies of phosphoinositide 3-kinases using free energy calculations",
abstract = "Phosphoinositide 3-kinases (PI3Ks) and their phosphatidylinositol 3,4,5-triphosphate (PIP3) products regulate a variety of cellular processes. Of these, PI3Kα is an attractive target for anticancer drug design. Mutations in the PI3Kα kinase domain alter the mobility of the activation loop resulting in gain of function. We employed molecular dynamics (MD) simulations-based energetic analysis using molecular mechanics/generalized born surface area (MM/GBSA) for PI3Kα and -γ. MD simulations were carried out for PI3K models based on the RESP (restrained electrostatic potential) and quantum mechanics (QM)-polarized ligand docking (QPLD)-derived partial charges. Computational alanine scanning was also used to evaluate the contributions of key binding residues to ligand binding. Our results show that both RESP and QPLD charge models of PI3Kα and PI3Kγ provide similar performance in MD simulations. For example, the predicted RESP and QPLD free energies of -9.5 and -9.3 kcal/mol for LY294002 binding to PI3Kγ and -10.9 and -11.7 kcal/mol for wortmannin binding to PI3Kα are in good agreement with experimental values. A significant loss in binding free energy was observed when hydrophobic residues were mutated to alanine, suggesting that specific hydrophobic interactions are important to optimal ligand binding. MM/GBSA calculations suggested that residues Ser774, Gln859, and Ile932 of PI3Kα might be used to design H1047R mutant-specific ligands, whereas Lys890 of PI3Kγ can be used for ligand design targeting PI3Kγ.",
author = "Sabbah, {Dima A.} and Vennerstrom, {Jonathan L} and Zhong, {Haizhen Andrew}",
year = "2012",
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AU - Sabbah, Dima A.

AU - Vennerstrom, Jonathan L

AU - Zhong, Haizhen Andrew

PY - 2012/12/21

Y1 - 2012/12/21

N2 - Phosphoinositide 3-kinases (PI3Ks) and their phosphatidylinositol 3,4,5-triphosphate (PIP3) products regulate a variety of cellular processes. Of these, PI3Kα is an attractive target for anticancer drug design. Mutations in the PI3Kα kinase domain alter the mobility of the activation loop resulting in gain of function. We employed molecular dynamics (MD) simulations-based energetic analysis using molecular mechanics/generalized born surface area (MM/GBSA) for PI3Kα and -γ. MD simulations were carried out for PI3K models based on the RESP (restrained electrostatic potential) and quantum mechanics (QM)-polarized ligand docking (QPLD)-derived partial charges. Computational alanine scanning was also used to evaluate the contributions of key binding residues to ligand binding. Our results show that both RESP and QPLD charge models of PI3Kα and PI3Kγ provide similar performance in MD simulations. For example, the predicted RESP and QPLD free energies of -9.5 and -9.3 kcal/mol for LY294002 binding to PI3Kγ and -10.9 and -11.7 kcal/mol for wortmannin binding to PI3Kα are in good agreement with experimental values. A significant loss in binding free energy was observed when hydrophobic residues were mutated to alanine, suggesting that specific hydrophobic interactions are important to optimal ligand binding. MM/GBSA calculations suggested that residues Ser774, Gln859, and Ile932 of PI3Kα might be used to design H1047R mutant-specific ligands, whereas Lys890 of PI3Kγ can be used for ligand design targeting PI3Kγ.

AB - Phosphoinositide 3-kinases (PI3Ks) and their phosphatidylinositol 3,4,5-triphosphate (PIP3) products regulate a variety of cellular processes. Of these, PI3Kα is an attractive target for anticancer drug design. Mutations in the PI3Kα kinase domain alter the mobility of the activation loop resulting in gain of function. We employed molecular dynamics (MD) simulations-based energetic analysis using molecular mechanics/generalized born surface area (MM/GBSA) for PI3Kα and -γ. MD simulations were carried out for PI3K models based on the RESP (restrained electrostatic potential) and quantum mechanics (QM)-polarized ligand docking (QPLD)-derived partial charges. Computational alanine scanning was also used to evaluate the contributions of key binding residues to ligand binding. Our results show that both RESP and QPLD charge models of PI3Kα and PI3Kγ provide similar performance in MD simulations. For example, the predicted RESP and QPLD free energies of -9.5 and -9.3 kcal/mol for LY294002 binding to PI3Kγ and -10.9 and -11.7 kcal/mol for wortmannin binding to PI3Kα are in good agreement with experimental values. A significant loss in binding free energy was observed when hydrophobic residues were mutated to alanine, suggesting that specific hydrophobic interactions are important to optimal ligand binding. MM/GBSA calculations suggested that residues Ser774, Gln859, and Ile932 of PI3Kα might be used to design H1047R mutant-specific ligands, whereas Lys890 of PI3Kγ can be used for ligand design targeting PI3Kγ.

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