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10.1039/d1cp00266j http://scihub22266oqcxt.onion/10.1039/d1cp00266j 33711090!ä!33711090 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 245.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 245.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 245.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       Phys+Chem+Chem+Phys 2021 ; 23 (11): 6746-6757 Nephropedia Template TP {{tp|p=33711090|t=2021. Covalent and non-covalent binding free energy calculations for peptidomimetic inhibitors of SARS-CoV-2 main protease |pdf=|usr=}}{{33711090}} gab.com Text Covalent and non-covalent binding free energy calculations for peptidomimetic inhibitors of SARS-CoV-2 main protease JO: Phys Chem Chem Phys http://www.kidney.de/pget.php?&tw=1&pmid=33711090 #FOAvip COVID-19, the disease caused by the newly discovered coronavirus-SARS-CoV-2, has created a global health, social, and economic crisis. As of mid-January 2021, there are over 90 million confirmed cases and more than 2 million reported deaths due to COVID-19. Currently, there are very limited therapeutics for the treatment or prevention of COVID-19. For this reason, it is important to find drug targets that will lead to the development of safe and effective therapeutics against the disease. The main protease (M(pro)) 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(pro) has no human homologues, so drugs designed to bind to this target directly have less risk for off-target effects. Recently, several high-resolution crystallographic structures of the M(pro) 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(pro), namely, N3 and alpha-ketoamide 13b. The total binding energy consists of both covalent and non-covalent binding components since both compounds are covalent inhibitors of the M(pro). Our results indicate that the covalent and non-covalent binding free energy contributions of both inhibitors to the M(pro) target differ significantly. The N3 inhibitor has more favourable non-covalent interactions, particularly hydrogen bonding, in the binding site of the M(pro) than the alpha-ketoamide inhibitor. Also, the Gibbs energy of reaction for the M(pro)-N3 covalent adduct is greater than the Gibbs reaction energy for the M(pro)-alpha-ketoamide 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 are consistent with the reversible and irreversible character of both inhibitors as reported by experiment and 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. This information could prove useful in the rational design, discovery, and evaluation of potent SARS-CoV-2 M(pro) inhibitors for targeted antiviral therapy. Twit Text FOAVip Covalent and non-covalent binding free energy calculations for peptidomimetic inhibitors of SARS-CoV-2 main protease ????Phys Chem Chem Phys http://www.kidney.de/pget.php?&tw=1&pmid=33711090 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=33711090 #FOAvip English Wikipedia <ref>{{Cite pmid|33711090}}</ref> Covalent and non-covalent binding free energy calculations for peptidomimetic inhibitors of SARS-CoV-2 main protease #MMPMID33711090 Awoonor-Williams E; Abu-Saleh AAA Phys Chem Chem Phys 2021[Mar]; 23 (11): 6746-6757 PMID33711090show ga COVID-19, the disease caused by the newly discovered coronavirus-SARS-CoV-2, has created a global health, social, and economic crisis. As of mid-January 2021, there are over 90 million confirmed cases and more than 2 million reported deaths due to COVID-19. Currently, there are very limited therapeutics for the treatment or prevention of COVID-19. For this reason, it is important to find drug targets that will lead to the development of safe and effective therapeutics against the disease. The main protease (M(pro)) 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(pro) has no human homologues, so drugs designed to bind to this target directly have less risk for off-target effects. Recently, several high-resolution crystallographic structures of the M(pro) 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(pro), namely, N3 and alpha-ketoamide 13b. The total binding energy consists of both covalent and non-covalent binding components since both compounds are covalent inhibitors of the M(pro). Our results indicate that the covalent and non-covalent binding free energy contributions of both inhibitors to the M(pro) target differ significantly. The N3 inhibitor has more favourable non-covalent interactions, particularly hydrogen bonding, in the binding site of the M(pro) than the alpha-ketoamide inhibitor. Also, the Gibbs energy of reaction for the M(pro)-N3 covalent adduct is greater than the Gibbs reaction energy for the M(pro)-alpha-ketoamide 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 are consistent with the reversible and irreversible character of both inhibitors as reported by experiment and 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. This information could prove useful in the rational design, discovery, and evaluation of potent SARS-CoV-2 M(pro) inhibitors for targeted antiviral therapy. |Amides/chemistry/metabolism[MESH] |Binding Sites[MESH] |COVID-19/pathology/virology[MESH] |Catalytic Domain[MESH] |Drug Design[MESH] |Humans[MESH] |Hydrogen-Ion Concentration[MESH] |Kinetics[MESH] |Ligands[MESH] |Molecular Dynamics Simulation[MESH] |Peptidomimetics/*chemistry/metabolism[MESH] |Protease Inhibitors/*chemistry/metabolism[MESH] |Quantum Theory[MESH] |SARS-CoV-2/*enzymology/isolation & purification[MESH] |Thermodynamics[MESH]Covalent and non-covalent binding free energy calculations for peptido(epmc).pdf DeepDyve Pubget Overpricing