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10.1021/acsnano.0c07383 http://scihub22266oqcxt.onion/10.1021/acsnano.0c07383 33373194!ä!33373194 Deprecated: Implicit conversion from float 235.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 235.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 235.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 235.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 235.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 269.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 269.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 269.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 269.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 269.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 302.79999999999995 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       ACS+Nano 2021 ; 15 (1): 857-872 Nephropedia Template TP {{tp|p=33373194|t=2021. Uncovering Flexible Active Site Conformations of SARS-CoV-2 3CL Proteases through Protease Pharmacophore Clusters and COVID-19 Drug Repurposing |pdf=|usr=}}{{33373194}} gab.com Text Uncovering Flexible Active Site Conformations of SARS-CoV-2 3CL Proteases through Protease Pharmacophore Clusters and COVID-19 Drug Repurposing JO: ACS Nano http://www.kidney.de/pget.php?&tw=1&pmid=33373194 #FOAvip The infectious SARS-CoV-2 causes COVID-19, which is now a global pandemic. Aiming for effective treatments, we focused on the key drug target, the viral 3C-like (3CL) protease. We modeled a big dataset with 42 SARS-CoV-2 3CL protease-ligand complex structures from approximately 98.7% similar SARS-CoV 3CL protease with abundant complex structures. The diverse flexible active site conformations identified in the dataset were clustered into six protease pharmacophore clusters (PPCs). For the PPCs with distinct flexible protease active sites and diverse interaction environments, we identified pharmacophore anchor hotspots. A total of 11 "PPC consensus anchors" (a distinct set observed in each PPC) were observed, of which three "PPC core anchors" EHV2, HV1, and V3 are strongly conserved across PPCs. The six PPC cavities were then applied in virtual screening of 2122 FDA drugs for repurposing, using core anchor-derived "PPC scoring S" to yield seven drug candidates. Experimental testing by SARS-CoV-2 3CL protease inhibition assay and antiviral cytopathic effect assays discovered active hits, Boceprevir and Telaprevir (HCV drugs) and Nelfinavir (HIV drug). Specifically, Boceprevir showed strong protease inhibition with micromolar IC(50) of 1.42 muM and an antiviral activity with EC(50) of 49.89 muM, whereas Telaprevir showed moderate protease inhibition only with an IC(50) of 11.47 muM. Nelfinavir solely showed antiviral activity with a micromolar EC(50) value of 3.28 muM. Analysis of binding mechanisms of protease inhibitors revealed the role of PPC core anchors. Our PPCs revealed the flexible protease active site conformations, which successfully enabled drug repurposing. Twit Text FOAVip Uncovering Flexible Active Site Conformations of SARS-CoV-2 3CL Proteases through Protease Pharmacophore Clusters and COVID-19 Drug Repurposing ????ACS Nano http://www.kidney.de/pget.php?&tw=1&pmid=33373194 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=33373194 #FOAvip English Wikipedia <ref>{{Cite pmid|33373194}}</ref> Uncovering Flexible Active Site Conformations of SARS-CoV-2 3CL Proteases through Protease Pharmacophore Clusters and COVID-19 Drug Repurposing #MMPMID33373194 Pathak N; Chen YT; Hsu YC; Hsu NY; Kuo CJ; Tsai HP; Kang JJ; Huang CH; Chang SY; Chang YH; Liang PH; Yang JM ACS Nano 2021[Jan]; 15 (1): 857-872 PMID33373194show ga The infectious SARS-CoV-2 causes COVID-19, which is now a global pandemic. Aiming for effective treatments, we focused on the key drug target, the viral 3C-like (3CL) protease. We modeled a big dataset with 42 SARS-CoV-2 3CL protease-ligand complex structures from approximately 98.7% similar SARS-CoV 3CL protease with abundant complex structures. The diverse flexible active site conformations identified in the dataset were clustered into six protease pharmacophore clusters (PPCs). For the PPCs with distinct flexible protease active sites and diverse interaction environments, we identified pharmacophore anchor hotspots. A total of 11 "PPC consensus anchors" (a distinct set observed in each PPC) were observed, of which three "PPC core anchors" EHV2, HV1, and V3 are strongly conserved across PPCs. The six PPC cavities were then applied in virtual screening of 2122 FDA drugs for repurposing, using core anchor-derived "PPC scoring S" to yield seven drug candidates. Experimental testing by SARS-CoV-2 3CL protease inhibition assay and antiviral cytopathic effect assays discovered active hits, Boceprevir and Telaprevir (HCV drugs) and Nelfinavir (HIV drug). Specifically, Boceprevir showed strong protease inhibition with micromolar IC(50) of 1.42 muM and an antiviral activity with EC(50) of 49.89 muM, whereas Telaprevir showed moderate protease inhibition only with an IC(50) of 11.47 muM. Nelfinavir solely showed antiviral activity with a micromolar EC(50) value of 3.28 muM. Analysis of binding mechanisms of protease inhibitors revealed the role of PPC core anchors. Our PPCs revealed the flexible protease active site conformations, which successfully enabled drug repurposing. |*COVID-19 Drug Treatment[MESH] |*Drug Repositioning[MESH] |Animals[MESH] |Antiviral Agents/pharmacology[MESH] |Catalytic Domain[MESH] |Chlorocebus aethiops[MESH] |Coronavirus 3C Proteases/*chemistry[MESH] |Drug Evaluation, Preclinical[MESH] |Humans[MESH] |Inhibitory Concentration 50[MESH] |Nelfinavir/pharmacology[MESH] |Oligopeptides/pharmacology[MESH] |Protease Inhibitors/pharmacology[MESH] |Protein Conformation[MESH] |SARS-CoV-2/*enzymology[MESH] |Spike Glycoprotein, Coronavirus/chemistry[MESH]Uncovering Flexible Active Site Conformations of SARS-CoV-2 3CL Protea(epmc).pdf DeepDyve Pubget Overpricing