scholarly journals Can Relative Binding Free Energy Predict Selectivity of Reversible Covalent Inhibitors?

2017 ◽  
Vol 139 (49) ◽  
pp. 17945-17952 ◽  
Author(s):  
Payal Chatterjee ◽  
Wesley M. Botello-Smith ◽  
Han Zhang ◽  
Li Qian ◽  
Abdelaziz Alsamarah ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Relative Binding ◽  
Covalent Inhibitors ◽  
Reversible Covalent

Predicting the affinity of halogenated reversible covalent inhibitors through relative binding free energy

2019 ◽  
Vol 21 (44) ◽  
pp. 24723-24730 ◽  
Author(s):  
Jerônimo Lameira ◽  
Vinícius Bonatto ◽  
Lorenzo Cianni ◽  
Fernanda dos Reis Rocho ◽  
Andrei Leitão ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Affinity ◽  
Binding Free Energy ◽  
Cathepsin L ◽  
Free Energy Perturbation ◽  
Relative Binding ◽  
Covalent Inhibitors ◽  
Human Cathepsin ◽  
Energy Perturbation ◽  
Reversible Covalent

The free energy perturbation using the covalent and noncovalent states can predict the binding affinity of covalent halogenated dipeptidyl nitrile inhibitors of the human Cathepsin L (hCatL).

scholarly journals Insight into the Binding Energetics of Targeted Reversible Covalent Inhibitors of the SARS-CoV-2 Main Protease

2021 ◽  
Author(s):  
Ernest Awoonor-Williams
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Replication Cycle ◽  
Energy Calculations ◽  
Main Protease ◽  
Binding Energetics ◽  
Covalent Inhibitors ◽  
Binding Free Energy Calculations ◽  
Reversible Covalent

The main protease (Mpro) of the SARS-CoV-2 virus is an attractive therapeutic target for developing antivirals to combat COVID-19. Mpro is essential for the replication cycle of the SARS-CoV-2 virus, so inhibiting Mpro blocks a vital piece of the cell replication machinery of the virus. A promising strategy to disrupt the viral replication cycle is to design inhibitors that bind to the active site cysteine (Cys145) of the Mpro. Cysteine targeted covalent inhibitors are gaining traction in drug discovery owing to the benefits of improved potency and extended drug-target engagement. An interesting aspect of these inhibitors is that they can be chemically tuned to form a covalent, but reversible bond, with their targets of interest. Several small-molecule cysteine-targeting covalent inhibitors of the Mpro have been discovered—some of which are currently undergoing evaluation in early phase human clinical trials. Understanding the binding energetics of these inhibitors could provide new insights to facilitate the design of potential drug candidates against COVID-19. Motivated by this, we employed rigorous absolute binding free energy calculations and hybrid quantum mechanical/molecular mechanical (QM/MM) calculations to estimate the energetics of binding of some promising reversible covalent inhibitors of the Mpro. We find that the inclusion of enhanced sampling techniques such as replica-exchange algorithm in binding free energy calculations can improve the convergence of predicted non-covalent binding free energy estimates of inhibitors binding to the Mpro target. In addition, our results indicate that binding free energy calculations coupled with multiscale simulations can be a useful approach to employ in ranking covalent inhibitors to their targets. This approach may be valuable in prioritizing and refining covalent inhibitor compounds for lead discovery efforts against COVID-19 and future coronavirus infections.

scholarly journals Insight into the Binding Energetics of Targeted Reversible Covalent Inhibitors of the SARS-CoV-2 Main Protease

2021 ◽  
Author(s):  
Ernest Awoonor-Williams
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Replication Cycle ◽  
Energy Calculations ◽  
Main Protease ◽  
Binding Energetics ◽  
Covalent Inhibitors ◽  
Binding Free Energy Calculations ◽  
Reversible Covalent

The main protease (Mpro) of the SARS-CoV-2 virus is an attractive therapeutic target for developing antivirals to combat COVID-19. Mpro is essential for the replication cycle of the SARS-CoV-2 virus, so inhibiting Mpro blocks a vital piece of the cell replication machinery of the virus. A promising strategy to disrupt the viral replication cycle is to design inhibitors that bind to the active site cysteine (Cys145) of the Mpro. Cysteine targeted covalent inhibitors are gaining traction in drug discovery owing to the benefits of improved potency and extended drug-target engagement. An interesting aspect of these inhibitors is that they can be chemically tuned to form a covalent, but reversible bond, with their targets of interest. Several small-molecule cysteine-targeting covalent inhibitors of the Mpro have been discovered—some of which are currently undergoing evaluation in early phase human clinical trials. Understanding the binding energetics of these inhibitors could provide new insights to facilitate the design of potential drug candidates against COVID-19. Motivated by this, we employed rigorous absolute binding free energy calculations and hybrid quantum mechanical/molecular mechanical (QM/MM) calculations to estimate the energetics of binding of some promising reversible covalent inhibitors of the Mpro. We find that the inclusion of enhanced sampling techniques such as replica-exchange algorithm in binding free energy calculations can improve the convergence of predicted non-covalent binding free energy estimates of inhibitors binding to the Mpro target. In addition, our results indicate that binding free energy calculations coupled with multiscale simulations can be a useful approach to employ in ranking covalent inhibitors to their targets. This approach may be valuable in prioritizing and refining covalent inhibitor compounds for lead discovery efforts against COVID-19 and future coronavirus infections.

scholarly journals TIES 20: Relative Binding Free Energy with a Flexible Superimposition Algorithm and Partial Ring Morphing

2021 ◽  
Vol 17 (2) ◽  
pp. 1250-1265
Author(s):  
Mateusz K. Bieniek ◽  
Agastya P. Bhati ◽  
Shunzhou Wan ◽  
Peter V. Coveney
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Relative Binding

scholarly journals Alchemical Free Energy Estimators and Molecular Dynamics Engines: Accuracy, Precision and Reproducibility

2021 ◽  
Author(s):  
Alexander Wade ◽  
Agastya Bhati ◽  
Shunzhou Wan ◽  
Peter Coveney
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Binding Free Energy ◽  
Thermodynamic Integration ◽  
Free Energy Perturbation ◽  
Free Energies ◽  
Ensemble Averaging ◽  
Relative Binding ◽  
Energy Perturbation ◽  
Binding Free Energies

The binding free energy between a ligand and its target protein is an essential quantity to know at all stages of the drug discovery pipeline. Assessing this value computationally can offer insight into where efforts should be focused in the pursuit of effective therapeutics to treat myriad diseases. In this work we examine the computation of alchemical relative binding free energies with an eye to assessing reproducibility across popular molecular dynamics packages and free energy estimators. The focus of this work is on 54 ligand transformations from a diverse set of protein targets: MCL1, PTP1B, TYK2, CDK2 and thrombin. These targets are studied with three popular molecular dynamics packages: OpenMM, NAMD2 and NAMD3. Trajectories collected with these packages are used to compare relative binding free energies calculated with thermodynamic integration and free energy perturbation methods. The resulting binding free energies show good agreement between molecular dynamics packages with an average mean unsigned error between packages of 0.5 $kcal/mol$ The correlation between packages is very good with the lowest Spearman's, Pearson's and Kendall's tau correlation coefficient between two packages being 0.91, 0.89 and 0.74 respectively. Agreement between thermodynamic integration and free energy perturbation is shown to be very good when using ensemble averaging.

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