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10.3390/v12090942 http://scihub22266oqcxt.onion/10.3390/v12090942 32859008!7552026!32859008     free     free     free Deprecated: Implicit conversion from float 227.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 227.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 227.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 227.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 227.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 227.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 227.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 261.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 261.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 261.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       Viruses 2020 ; 12 (9): ä Nephropedia Template TP {{tp|p=32859008|t=2020. Optimization Rules for SARS-CoV-2 M(pro) Antivirals: Ensemble Docking and Exploration of the Coronavirus Protease Active Site |pdf=|usr=}}{{32859008}} gab.com Text Optimization Rules for SARS-CoV-2 M(pro) Antivirals: Ensemble Docking and Exploration of the Coronavirus Protease Active Site JO: Viruses http://www.kidney.de/pget.php?&tw=1&pmid=32859008 #FOAvip Coronaviruses are viral infections that have a significant ability to impact human health. Coronaviruses have produced two pandemics and one epidemic in the last two decades. The current pandemic has created a worldwide catastrophe threatening the lives of over 15 million as of July 2020. Current research efforts have been focused on producing a vaccine or repurposing current drug compounds to develop a therapeutic. There is, however, a need to study the active site preferences of relevant targets, such as the SARS-CoV-2 main protease (SARS-CoV-2 M(pro)), to determine ways to optimize these drug compounds. The ensemble docking and characterization work described in this article demonstrates the multifaceted features of the SARS-CoV-2 M(pro) active site, molecular guidelines to improving binding affinity, and ultimately the optimization of drug candidates. A total of 220 compounds were docked into both the 5R7Z and 6LU7 SARS-CoV-2 M(pro) crystal structures. Several key preferences for strong binding to the four subsites (S1, S1', S2, and S4) were identified, such as accessing hydrogen binding hotspots, hydrophobic patches, and utilization of primarily aliphatic instead of aromatic substituents. After optimization efforts using the design guidelines developed from the molecular docking studies, the average docking score of the parent compounds was improved by 6.59 -log(10)(Kd) in binding affinity which represents an increase of greater than six orders of magnitude. Using the optimization guidelines, the SARS-CoV-2 M(pro) inhibitor cinanserin was optimized resulting in an increase in binding affinity of 4.59 -log(10)(Kd) and increased protease inhibitor bioactivity. The results of molecular dynamic (MD) simulation of cinanserin-optimized compounds CM02, CM06, and CM07 revealed that CM02 and CM06 fit well into the active site of SARS-CoV-2 M(pro) [Protein Data Bank (PDB) accession number 6LU7] and formed strong and stable interactions with the key residues, Ser-144, His-163, and Glu-166. The enhanced binding affinity produced demonstrates the utility of the design guidelines described. The work described herein will assist scientists in developing potent COVID-19 antivirals. Twit Text FOAVip Optimization Rules for SARS-CoV-2 M(pro) Antivirals: Ensemble Docking and Exploration of the Coronavirus Protease Active Site ????Viruses http://www.kidney.de/pget.php?&tw=1&pmid=32859008 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=32859008 #FOAvip English Wikipedia <ref>{{Cite pmid|32859008}}</ref> Optimization Rules for SARS-CoV-2 M(pro) Antivirals: Ensemble Docking and Exploration of the Coronavirus Protease Active Site #MMPMID32859008 Stoddard SV; Stoddard SD; Oelkers BK; Fitts K; Whalum K; Whalum K; Hemphill AD; Manikonda J; Martinez LM; Riley EG; Roof CM; Sarwar N; Thomas DM; Ulmer E; Wallace FE; Pandey P; Roy S Viruses 2020[Aug]; 12 (9): ä PMID32859008show ga Coronaviruses are viral infections that have a significant ability to impact human health. Coronaviruses have produced two pandemics and one epidemic in the last two decades. The current pandemic has created a worldwide catastrophe threatening the lives of over 15 million as of July 2020. Current research efforts have been focused on producing a vaccine or repurposing current drug compounds to develop a therapeutic. There is, however, a need to study the active site preferences of relevant targets, such as the SARS-CoV-2 main protease (SARS-CoV-2 M(pro)), to determine ways to optimize these drug compounds. The ensemble docking and characterization work described in this article demonstrates the multifaceted features of the SARS-CoV-2 M(pro) active site, molecular guidelines to improving binding affinity, and ultimately the optimization of drug candidates. A total of 220 compounds were docked into both the 5R7Z and 6LU7 SARS-CoV-2 M(pro) crystal structures. Several key preferences for strong binding to the four subsites (S1, S1', S2, and S4) were identified, such as accessing hydrogen binding hotspots, hydrophobic patches, and utilization of primarily aliphatic instead of aromatic substituents. After optimization efforts using the design guidelines developed from the molecular docking studies, the average docking score of the parent compounds was improved by 6.59 -log(10)(Kd) in binding affinity which represents an increase of greater than six orders of magnitude. Using the optimization guidelines, the SARS-CoV-2 M(pro) inhibitor cinanserin was optimized resulting in an increase in binding affinity of 4.59 -log(10)(Kd) and increased protease inhibitor bioactivity. The results of molecular dynamic (MD) simulation of cinanserin-optimized compounds CM02, CM06, and CM07 revealed that CM02 and CM06 fit well into the active site of SARS-CoV-2 M(pro) [Protein Data Bank (PDB) accession number 6LU7] and formed strong and stable interactions with the key residues, Ser-144, His-163, and Glu-166. The enhanced binding affinity produced demonstrates the utility of the design guidelines described. The work described herein will assist scientists in developing potent COVID-19 antivirals. |Antiviral Agents/chemistry/*pharmacology[MESH] |Betacoronavirus/*drug effects/enzymology[MESH] |Binding Sites[MESH] |COVID-19[MESH] |Catalytic Domain[MESH] |Coronavirus 3C Proteases[MESH] |Coronavirus Infections/*drug therapy/*virology[MESH] |Cysteine Endopeptidases/chemistry/*metabolism[MESH] |Drug Design[MESH] |Drug Repositioning[MESH] |Humans[MESH] |Molecular Docking Simulation/methods[MESH] |Molecular Dynamics Simulation[MESH] |Pandemics[MESH] |Pneumonia, Viral/*drug therapy/*virology[MESH] |Protease Inhibitors/chemistry/*pharmacology[MESH] |Protein Conformation[MESH] |SARS-CoV-2[MESH]Optimization Rules for SARS-CoV-2 M(pro) Antivirals: Ensemble Docking (epmc).pdf DeepDyve Pubget Overpricing