Covalent and non-covalent binding free energy calculations of peptidometic inhibitors of SARS-CoV-2 main protease

2021 ◽  
Author(s):  
Ernest Awoonor-Williams ◽  
Abd Al-Aziz Abu-Saleh ◽  
Christopher Rowley
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Covalent Binding ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
Main Protease ◽  
Binding Free Energy Calculations

Covalent and non-covalent binding free energy calculations for peptidomimetic inhibitors of SARS-CoV-2 main protease

2021 ◽  
Author(s):  
Ernest Awoonor-Williams ◽  
Abd Al-Aziz A. Abu-Saleh
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Covalent Binding ◽  
Free Energy Calculations ◽  
Total Binding Energy ◽  
Energy Calculations ◽  
Main Protease ◽  
Covalent Inhibitors ◽  
Binding Free Energy Calculations ◽  
Absolute Binding Free Energy

This work employs rigorous absolute binding free energy calculations and QM/MM methods to calculate the total binding energy of two recently crystallized peptidomimetic covalent inhibitors of the SARS-CoV-2 Mpro target.

scholarly journals Identification of antiviral phytochemicals as a potential SARS-CoV-2 main protease (Mpro) inhibitor using docking and molecular dynamics simulations

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chirag N. Patel ◽  
Siddhi P. Jani ◽  
Dharmesh G. Jaiswal ◽  
Sivakumar Prasanth Kumar ◽  
Naman Mangukia ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Natural Compounds ◽  
Free Energy Calculations ◽  
Public Health Care ◽  
Dynamic Simulations ◽  
Energy Calculations ◽  
Main Protease ◽  
Binding Free Energy Calculations ◽  
Dynamics Simulations

AbstractNovel SARS-CoV-2, an etiological factor of Coronavirus disease 2019 (COVID-19), poses a great challenge to the public health care system. Among other druggable targets of SARS-Cov-2, the main protease (Mpro) is regarded as a prominent enzyme target for drug developments owing to its crucial role in virus replication and transcription. We pursued a computational investigation to identify Mpro inhibitors from a compiled library of natural compounds with proven antiviral activities using a hierarchical workflow of molecular docking, ADMET assessment, dynamic simulations and binding free-energy calculations. Five natural compounds, Withanosides V and VI, Racemosides A and B, and Shatavarin IX, obtained better binding affinity and attained stable interactions with Mpro key pocket residues. These intermolecular key interactions were also retained profoundly in the simulation trajectory of 100 ns time scale indicating tight receptor binding. Free energy calculations prioritized Withanosides V and VI as the top candidates that can act as effective SARS-CoV-2 Mpro inhibitors.

scholarly journals Covalent and Non-Covalent Binding Free Energy Calculations for Peptidomimetic Inhibitors of SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Ernest Awoonor-Williams ◽  
Abd Al-Aziz A. Abu-Saleh
Keyword(s):  
Free Energy ◽  
Drug Design ◽  
Binding Free Energy ◽  
Covalent Binding ◽  
Free Energy Calculations ◽  
Total Binding Energy ◽  
Structure Based Drug Design ◽  
Main Protease ◽  
Covalent Adduct ◽  
Binding Free Energy Calculations

COVID-19, the disease caused by the newly discovered coronavirus — SARS-CoV-2, has created global health, social, and economic crisis. At the time of writing (November 12, 2020), there are over 50 million confirmed cases and more than 1 million reported deaths due to COVID-19. Currently, there are no approved vaccines, and recently Veklury (remdesivir) was approved for the treatment of COVID-19 requiring hospitalization. The main protease (M<sup>pro</sup>) of the virus is an attractive target for the development of effective antiviral therapeutics because it is required for proteolytic cleavage of viral polyproteins. Furthermore, the M<sup>pro</sup> has no human homologues, so drugs designed to bind to this target directly have less risk for off-target reactivity. Recently, several high-resolution crystallographic structures of the M<sup>pro</sup> in complex with inhibitors have been determined — to guide drug development and to spur efforts in structure-based drug design. One of the primary objectives of modern structure-based drug design is the accurate prediction of receptor­-ligand binding affinities for rational drug design and discovery. Here, we perform rigorous alchemical absolute binding free energy calculations and QM/MM calculations to give insight into the total binding energy of two recently crystallized inhibitors of SARS-CoV-2 M<sup>pro</sup>, namely, N3 and α-ketoamide 13b. The total binding energy consists of both covalent and non-covalent binding components since both compounds are covalent inhibitors of the M<sup>pro</sup>. Our results indicate that the covalent and non-covalent binding free energy contributions of both inhibitors to the M<sup>pro</sup> target differ significantly. The N3 inhibitor has more favourable non-covalent interactions, particularly hydrogen bonding, in the binding site of the M<sup>pro</sup> than the α-ketoamide inhibitor. But the Gibbs energy of reaction for the M<sup>pro</sup>–α-ketoamide covalent adduct is greater than the Gibbs reaction energy for the M<sup>pro</sup>–N3 covalent adduct. These differences in the covalent and non-covalent binding free energy contributions for both inhibitors could be a plausible explanation for their in vitro differences in antiviral activity. Our findings highlight the importance of both covalent and non-covalent binding free energy contributions to the absolute binding affinity of a covalent inhibitor towards its target.

scholarly journals Covalent and Non-Covalent Binding Free Energy Calculations for Peptidomimetic Inhibitors of SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Ernest Awoonor-Williams ◽  
Abd Al-Aziz A. Abu-Saleh
Keyword(s):  
Free Energy ◽  
Drug Design ◽  
Binding Free Energy ◽  
Covalent Binding ◽  
Free Energy Calculations ◽  
Total Binding Energy ◽  
Structure Based Drug Design ◽  
Main Protease ◽  
Covalent Adduct ◽  
Binding Free Energy Calculations

COVID-19, the disease caused by the newly discovered coronavirus — SARS-CoV-2, has created global health, social, and economic crisis. At the time of writing (November 12, 2020), there are over 50 million confirmed cases and more than 1 million reported deaths due to COVID-19. Currently, there are no approved vaccines, and recently Veklury (remdesivir) was approved for the treatment of COVID-19 requiring hospitalization. The main protease (M<sup>pro</sup>) of the virus is an attractive target for the development of effective antiviral therapeutics because it is required for proteolytic cleavage of viral polyproteins. Furthermore, the M<sup>pro</sup> has no human homologues, so drugs designed to bind to this target directly have less risk for off-target reactivity. Recently, several high-resolution crystallographic structures of the M<sup>pro</sup> in complex with inhibitors have been determined — to guide drug development and to spur efforts in structure-based drug design. One of the primary objectives of modern structure-based drug design is the accurate prediction of receptor­-ligand binding affinities for rational drug design and discovery. Here, we perform rigorous alchemical absolute binding free energy calculations and QM/MM calculations to give insight into the total binding energy of two recently crystallized inhibitors of SARS-CoV-2 M<sup>pro</sup>, namely, N3 and α-ketoamide 13b. The total binding energy consists of both covalent and non-covalent binding components since both compounds are covalent inhibitors of the M<sup>pro</sup>. Our results indicate that the covalent and non-covalent binding free energy contributions of both inhibitors to the M<sup>pro</sup> target differ significantly. The N3 inhibitor has more favourable non-covalent interactions, particularly hydrogen bonding, in the binding site of the M<sup>pro</sup> than the α-ketoamide inhibitor. But the Gibbs energy of reaction for the M<sup>pro</sup>–α-ketoamide covalent adduct is greater than the Gibbs reaction energy for the M<sup>pro</sup>–N3 covalent adduct. These differences in the covalent and non-covalent binding free energy contributions for both inhibitors could be a plausible explanation for their in vitro differences in antiviral activity. Our findings highlight the importance of both covalent and non-covalent binding free energy contributions to the absolute binding affinity of a covalent inhibitor towards its target.

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 Automation of absolute protein-ligand binding free energy calculations for docking refinement and compound evaluation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Germano Heinzelmann ◽  
Michael K. Gilson
Keyword(s):  
Free Energy ◽  
Early Stage ◽  
Binding Free Energy ◽  
Low Cost ◽  
Free Energy Calculations ◽  
Free Energies ◽  
Energy Calculations ◽  
Drug Candidates ◽  
Binding Free Energy Calculations ◽  
Binding Free Energies

AbstractAbsolute binding free energy calculations with explicit solvent molecular simulations can provide estimates of protein-ligand affinities, and thus reduce the time and costs needed to find new drug candidates. However, these calculations can be complex to implement and perform. Here, we introduce the software BAT.py, a Python tool that invokes the AMBER simulation package to automate the calculation of binding free energies for a protein with a series of ligands. The software supports the attach-pull-release (APR) and double decoupling (DD) binding free energy methods, as well as the simultaneous decoupling-recoupling (SDR) method, a variant of double decoupling that avoids numerical artifacts associated with charged ligands. We report encouraging initial test applications of this software both to re-rank docked poses and to estimate overall binding free energies. We also show that it is practical to carry out these calculations cheaply by using graphical processing units in common machines that can be built for this purpose. The combination of automation and low cost positions this procedure to be applied in a relatively high-throughput mode and thus stands to enable new applications in early-stage drug discovery.

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