Automated Assessment of Binding Affinity via Alchemical Free Energy Calculations

2020 ◽  
Author(s):  
Maximilian Kuhn ◽  
Stuart Firth-Clark ◽  
Paolo Tosco ◽  
Antonia S. J. S. Mey ◽  
Mark Mackey ◽  
...  
Keyword(s):  
Free Energy ◽  
Protein Structures ◽  
Free Energy Calculations ◽  
Distinct Advantage ◽  
Binding Affinities ◽  
Structure Based Drug Design ◽  
Energy Calculations ◽  
Kendall’S Τ ◽  
Experimental Values ◽  
Better Than

Free energy calculations have seen increased usage in structure-based drug design. Despite the rising interest, automation of the complex calculations and subsequent analysis of their results are still hampered by the restricted choice of available tools. In this work, an application for automated setup and processing of free energy calculations is presented. Several sanity checks for assessing the reliability of the calculations were implemented, constituting a distinct advantage over existing open-source tools. The underlying workflow is built on top of the software Sire, SOMD, BioSimSpace and OpenMM and uses the AMBER14SB and GAFF2.1 force fields. It was validated on two datasets originally composed by Schrödinger, consisting of 14 protein structures and 220 ligands. Predicted binding affinities were in good agreement with experimental values. For the larger dataset the average correlation coefficient Rp was 0.70 ± 0.05 and average Kendall’s τ was 0.53 ± 0.05 which is broadly comparable to or better than previously reported results using other methods. <br>

Automated Assessment of Binding Affinity via Alchemical Free Energy Calculations

2020 ◽  
Author(s):  
Maximilian Kuhn ◽  
Stuart Firth-Clark ◽  
Paolo Tosco ◽  
Antonia S. J. S. Mey ◽  
Mark Mackey ◽  
...  
Keyword(s):  
Free Energy ◽  
Protein Structures ◽  
Free Energy Calculations ◽  
Distinct Advantage ◽  
Binding Affinities ◽  
Structure Based Drug Design ◽  
Energy Calculations ◽  
Kendall’S Τ ◽  
Experimental Values ◽  
Better Than

Free energy calculations have seen increased usage in structure-based drug design. Despite the rising interest, automation of the complex calculations and subsequent analysis of their results are still hampered by the restricted choice of available tools. In this work, an application for automated setup and processing of free energy calculations is presented. Several sanity checks for assessing the reliability of the calculations were implemented, constituting a distinct advantage over existing open-source tools. The underlying workflow is built on top of the software Sire, SOMD, BioSimSpace and OpenMM and uses the AMBER14SB and GAFF2.1 force fields. It was validated on two datasets originally composed by Schrödinger, consisting of 14 protein structures and 220 ligands. Predicted binding affinities were in good agreement with experimental values. For the larger dataset the average correlation coefficient Rp was 0.70 ± 0.05 and average Kendall’s τ was 0.53 ± 0.05 which is broadly comparable to or better than previously reported results using other methods. <br>

Free Energy Calculations to Estimate Ligand-Binding Affinities in Structure-Based Drug Design

2014 ◽  
Vol 20 (20) ◽  
pp. 3323-3337 ◽  
Author(s):  
M. Reddy ◽  
C. Reddy ◽  
R. Rathore ◽  
Mark Erion ◽  
P. Aparoy ◽  
...  
Keyword(s):  
Free Energy ◽  
Drug Design ◽  
Ligand Binding ◽  
Free Energy Calculations ◽  
Binding Affinities ◽  
Structure Based Drug Design ◽  
Energy Calculations

Rigorous Free Energy Calculations in Structure-Based Drug Design

2010 ◽  
Vol 29 (8-9) ◽  
pp. 570-578 ◽  
Author(s):  
Julien Michel ◽  
Nicolas Foloppe ◽  
Jonathan W. Essex
Keyword(s):  
Free Energy ◽  
Drug Design ◽  
Free Energy Calculations ◽  
Structure Based Drug Design ◽  
Energy Calculations

scholarly journals SAMPL7 TrimerTrip Host-Guest Binding Affinities from Extensive Alchemical and End-Point Free Energy Calculations

2020 ◽  
Author(s):  
Zhe Huai ◽  
Huaiyu Yang ◽  
Xiao Li ◽  
Zhaoxi Sun
Keyword(s):  
Free Energy ◽  
Computational Modelling ◽  
Free Energy Calculations ◽  
Binding Affinities ◽  
Enhanced Sampling ◽  
New Host ◽  
Energy Calculations ◽  
Configurational Space ◽  
End Point ◽  
Guest Binding

<p>The prediction of host-guest binding affinities with computational modelling is still a challenging task. In the 7<sup>th</sup> statistical assessment of the modeling of proteins and ligands (SAMPL) challenge, a new host named TrimerTrip is synthesized and the thermodynamic parameters of 16 structurally diverse guests binding to the host are characterized. The challenge provides only structures of the host and the guests, which indicates that the predictions of both the binding poses and the binding affinities are under assessment. In this work, starting from the binding poses obtained from our previous enhanced sampling simulations in the configurational space, we perform extensive alchemical and end-point free energy calculations to calculate the host-guest binding affinities. The alchemical predictions with two widely accepted charge schemes (i.e. AM1-BCC and RESP) are in good agreement with the experimental reference, while the end-point estimates show significant deviations. Surprisingly, the end-point MM/PBSA method seems very powerful in reproducing the experimental rank of binding affinities. Although the length of our simulations is already very long and the intermediate spacing is very dense, the convergence behavior is not very good, which may arise from the flexibility of the host molecule. Enhanced sampling techniques in the configurational space may be required to obtain fully converged sampling. Further, as the length of sampling in alchemical free energy calculations already achieves several hundred ns, performing direct simulations of the binding/unbinding event in the physical space could be more useful and insightful. More details about the binding pathway and mechanism could be obtained in this way. </p>

Free-energy calculations in structure-based drug design

Drug Design ◽  
2010 ◽  
pp. 61-86 ◽  
Author(s):  
Michael R. Shirts ◽  
David L. Mobley ◽  
Scott P. Brown
Keyword(s):  
Free Energy ◽  
Drug Design ◽  
Free Energy Calculations ◽  
Structure Based Drug Design ◽  
Energy Calculations

scholarly journals SAMPL7 TrimerTrip Host-Guest Binding Affinities from Extensive Alchemical and End-Point Free Energy Calculations

2020 ◽  
Author(s):  
Zhe Huai ◽  
Huaiyu Yang ◽  
Xiao Li ◽  
Zhaoxi Sun
Keyword(s):  
Free Energy ◽  
Computational Modelling ◽  
Free Energy Calculations ◽  
Binding Affinities ◽  
Enhanced Sampling ◽  
New Host ◽  
Energy Calculations ◽  
Configurational Space ◽  
End Point ◽  
Guest Binding

<p></p><p> The prediction of host-guest binding affinities with computational modelling is still a challenging task. In the 7<sup>th</sup> statistical assessment of the modeling of proteins and ligands (SAMPL) challenge, a new host named TrimerTrip was synthesized and the thermodynamic parameters of 16 structurally diverse guests binding to the host were characterized. In the TrimerTrip-guest challenge, only structures of the host and the guests are provided, which indicates that the predictions of both the binding poses and the binding affinities are under assessment. In this work, starting from the binding poses obtained from our previous enhanced sampling simulations in the configurational space, we perform extensive alchemical and end-point free energy calculations to calculate the host-guest binding affinities retrospectively. The alchemical predictions with two widely accepted charge schemes (i.e. AM1-BCC and RESP) are in good agreement with the experimental reference, while the end-point estimates perform poorly in reproducing the experimental binding affinities. Aside from the absolute value of the binding affinity, the rank of binding free energies is also crucial in drug design. Surprisingly, the end-point MM/PBSA method seems very powerful in reproducing the experimental rank of binding affinities. Although the length of our simulations is long and the intermediate spacing is dense, the convergence behavior is not very good, which may arise from the flexibility of the host molecule. Enhanced sampling techniques in the configurational space may be required to obtain fully converged sampling. Further, as the length of sampling in alchemical free energy calculations already achieves several hundred ns, performing direct simulations of the binding/unbinding event in the physical space could be more useful and insightful. More details about the binding pathway and mechanism could be obtained in this way. The nonequilibrium method could also be a nice choice if one insists to use the alchemical method, as the intermediate sampling is avoided to some extent. </p><p></p>

scholarly journals SAMPL7 TrimerTrip Host-Guest Binding Affinities from Extensive Alchemical and End-Point Free Energy Calculations

2020 ◽  
Author(s):  
Zhe Huai ◽  
Huaiyu Yang ◽  
Xiao Li ◽  
Zhaoxi Sun
Keyword(s):  
Free Energy ◽  
Computational Modelling ◽  
Free Energy Calculations ◽  
Binding Affinities ◽  
Enhanced Sampling ◽  
New Host ◽  
Energy Calculations ◽  
Configurational Space ◽  
End Point ◽  
Guest Binding

<p></p><p> The prediction of host-guest binding affinities with computational modelling is still a challenging task. In the 7<sup>th</sup> statistical assessment of the modeling of proteins and ligands (SAMPL) challenge, a new host named TrimerTrip was synthesized and the thermodynamic parameters of 16 structurally diverse guests binding to the host were characterized. In the TrimerTrip-guest challenge, only structures of the host and the guests are provided, which indicates that the predictions of both the binding poses and the binding affinities are under assessment. In this work, starting from the binding poses obtained from our previous enhanced sampling simulations in the configurational space, we perform extensive alchemical and end-point free energy calculations to calculate the host-guest binding affinities retrospectively. The alchemical predictions with two widely accepted charge schemes (i.e. AM1-BCC and RESP) are in good agreement with the experimental reference, while the end-point estimates perform poorly in reproducing the experimental binding affinities. Aside from the absolute value of the binding affinity, the rank of binding free energies is also crucial in drug design. Surprisingly, the end-point MM/PBSA method seems very powerful in reproducing the experimental rank of binding affinities. Although the length of our simulations is long and the intermediate spacing is dense, the convergence behavior is not very good, which may arise from the flexibility of the host molecule. Enhanced sampling techniques in the configurational space may be required to obtain fully converged sampling. Further, as the length of sampling in alchemical free energy calculations already achieves several hundred ns, performing direct simulations of the binding/unbinding event in the physical space could be more useful and insightful. More details about the binding pathway and mechanism could be obtained in this way. The nonequilibrium method could also be a nice choice if one insists to use the alchemical method, as the intermediate sampling is avoided to some extent. </p><p></p>

Computation of the binding affinities of catechol-O-methyltransferase inhibitors: Multisubstate relative free energy calculations

2012 ◽  
Vol 33 (9) ◽  
pp. 970-986 ◽  
Author(s):  
P. Nuno Palma ◽  
Maria João Bonifácio ◽  
Ana Isabel Loureiro ◽  
Patrício Soares-da-Silva
Keyword(s):  
Free Energy ◽  
Free Energy Calculations ◽  
Binding Affinities ◽  
Energy Calculations ◽  
Relative Free Energy
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