Large-Scale Assessment of Binding Free Energy Calculations in Active Drug Discovery Projects

2020 ◽  
Vol 60 (11) ◽  
pp. 5457-5474 ◽  
Author(s):  
Christina E. M. Schindler ◽  
Hannah Baumann ◽  
Andreas Blum ◽  
Dietrich Böse ◽  
Hans-Peter Buchstaller ◽  
...  
Keyword(s):  
Free Energy ◽  
Drug Discovery ◽  
Large Scale ◽  
Active Drug ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
Large Scale Assessment ◽  
Scale Assessment ◽  
Binding Free Energy Calculations

Large-Scale Assessment of Binding Free Energy Calculations in Active Drug Discovery Projects

2020 ◽  
Author(s):  
Christina Schindler ◽  
Hannah Baumann ◽  
Andreas Blum ◽  
Dietrich Böse ◽  
Hans-Peter Buchstaller ◽  
...  
Keyword(s):  
Free Energy ◽  
Drug Discovery ◽  
Large Scale ◽  
Active Drug ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Energy Calculation ◽  
Large Scale Assessment ◽  
New Public ◽  
Binding Free Energy Calculations

Here we present an evaluation of the binding affinity prediction accuracy of the free energy calculation method FEP+ on internal active drug discovery projects and on a large new public benchmark set.<br>

Large-Scale Assessment of Binding Free Energy Calculations in Active Drug Discovery Projects

2020 ◽  
Author(s):  
Christina Schindler ◽  
Hannah Baumann ◽  
Andreas Blum ◽  
Dietrich Böse ◽  
Hans-Peter Buchstaller ◽  
...  
Keyword(s):  
Free Energy ◽  
Drug Discovery ◽  
Large Scale ◽  
Active Drug ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Energy Calculation ◽  
Large Scale Assessment ◽  
New Public ◽  
Binding Free Energy Calculations

Here we present an evaluation of the binding affinity prediction accuracy of the free energy calculation method FEP+ on internal active drug discovery projects and on a large new public benchmark set.<br>

Large-Scale Assessment of Binding Free Energy Calculations in Active Drug Discovery Projects

2020 ◽  
Author(s):  
Christina Schindler ◽  
Hannah Baumann ◽  
Andreas Blum ◽  
Dietrich Böse ◽  
Hans-Peter Buchstaller ◽  
...  
Keyword(s):  
Free Energy ◽  
Drug Discovery ◽  
Large Scale ◽  
Active Drug ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Energy Calculation ◽  
Large Scale Assessment ◽  
New Public ◽  
Binding Free Energy Calculations

Here we present an evaluation of the binding affinity prediction accuracy of the free energy calculation method FEP+ on internal active drug discovery projects and on a large new public benchmark set.<br>

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...

scholarly journals Alchemical Binding Free Energy Calculations in AMBER20: Advances and Best Practices for Drug Discovery

2020 ◽  
Vol 60 (11) ◽  
pp. 5595-5623 ◽  
Author(s):  
Tai-Sung Lee ◽  
Bryce K. Allen ◽  
Timothy J. Giese ◽  
Zhenyu Guo ◽  
Pengfei Li ◽  
...  
Keyword(s):  
Free Energy ◽  
Drug Discovery ◽  
Best Practices ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
Binding Free Energy Calculations

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

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

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 a challenging endeavour, mostly limited to small model cases. Here, we demonstrate accurate first principles based absolute binding free energy estimates for 128 pharmaceutically relevant targets. We use a novel rigorous method to generate protein-ligand ensembles for the ligand in its decoupled state. Not only do the calculations deliver accurate protein-ligand binding affinity estimates, but they also provide detailed physical insight into the structural determinants of binding. We identify subtle rotamer rearrangements between apo and holo states of a protein that are crucial for binding. When compared to relative binding free energy calculations, obtaining absolute binding free energies is considerably more challenging in large part due to the need to explicitly account for the protein in its apo state. In this work we present several approaches to obtain apo state ensembles for accurate absolute ΔG calculations, thus outlining protocols for prospective application of the methods for drug discovery.

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