Modelling flexible protein–ligand binding in p38α MAP kinase using the QUBE force field

2020 ◽  
Vol 56 (6) ◽  
pp. 932-935 ◽  
Author(s):  
Joshua T. Horton ◽  
Alice E. A. Allen ◽  
Daniel J. Cole
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Force Field ◽  
Map Kinase ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Quantum Mechanical ◽  
Flexible Protein ◽  
Binding Free Energy Calculations ◽  
P38α Map Kinase

The accuracy of quantum mechanical bespoke (QUBE) force fields for protein–ligand binding free energy calculations are benchmarked against experiment.

Modelling Flexible Protein-Ligand Binding in p38α MAP Kinase using the QUBE Force Field

2019 ◽  
Author(s):  
Joshua Horton ◽  
Alice Allen ◽  
Daniel Cole
Keyword(s):  
Quantum Mechanics ◽  
Force Field ◽  
Map Kinase ◽  
Binding Free Energy ◽  
Quantum Mechanical ◽  
Enhanced Sampling ◽  
Relative Binding ◽  
Stringent Test ◽  
Flexible Protein ◽  
P38α Map Kinase

<div><div><div><p>The quantum mechanical bespoke (QUBE) force field is used to retrospectively calculate the relative binding free energy of a series of 17 flexible inhibitors of p38α MAP kinase. The size and flexibility of the chosen molecules represent a stringent test of the derivation of force field parameters from quantum mechanics, and enhanced sampling is required to reduce the dependence of the results on the starting structure. Competitive accuracy with a widely-used biological force field is achieved, indicating that quantum mechanics derived force fields are approaching the accuracy required to provide guidance in prospective drug discovery campaigns.</p></div></div></div>

scholarly journals Modelling Flexible Protein-Ligand Binding in p38α MAP Kinase using the QUBE Force Field

2019 ◽  
Author(s):  
Joshua Horton ◽  
Alice Allen ◽  
Daniel Cole
Keyword(s):  
Quantum Mechanics ◽  
Force Field ◽  
Map Kinase ◽  
Binding Free Energy ◽  
Quantum Mechanical ◽  
Enhanced Sampling ◽  
Relative Binding ◽  
Stringent Test ◽  
Flexible Protein ◽  
P38α Map Kinase

<div><div><div><p>The quantum mechanical bespoke (QUBE) force field is used to retrospectively calculate the relative binding free energy of a series of 17 flexible inhibitors of p38α MAP kinase. The size and flexibility of the chosen molecules represent a stringent test of the derivation of force field parameters from quantum mechanics, and enhanced sampling is required to reduce the dependence of the results on the starting structure. Competitive accuracy with a widely-used biological force field is achieved, indicating that quantum mechanics derived force fields are approaching the accuracy required to provide guidance in prospective drug discovery campaigns.</p></div></div></div>

scholarly journals Alchemical Absolute Protein-Ligand Binding Free Energies for Drug Design

2021 ◽  
Author(s):  
Yuriy Khalak ◽  
Gary Tresdern ◽  
Matteo Aldeghi ◽  
Hannah Magdalena Baumann ◽  
David L. Mobley ◽  
...  
Keyword(s):  
Free Energy ◽  
Drug Discovery ◽  
Drug Design ◽  
Ligand Binding ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Free Energies ◽  
Energy Calculations ◽  
Binding Free Energy Calculations ◽  
Binding Free Energies

The recent advances in relative protein-ligand binding free energy calculations have shown the value of alchemical methods in drug discovery. Accurately assessing absolute binding free energies, although highly desired, remains...

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