PMC:7755033 / 71143-77335 JSONTXT

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67.23 nM), SARS-CoV-2 spike glycoprotein (Table 7; BE: −7.18 kcal/mol, Kd: 5.48 µM), SARS-CoV 3CL-pro main protease (Table 9; BE: –8.93 kcal/mol, Kd: 285.01 nM) and SARS-CoV-2 Nsp10/Nsp-16 complex (Table 11; BE: −10.38 kcal/mol, Kd: 24.67 nM). Interestingly, withanolide A exhibited almost 1000× times stronger binding to SARS-CoV main protease as compared to standard reference drugs arbidol (Table 6; BE: −4.91 kcal/mol, Kd: 251.65 µM) and hydroxychloroquine (Table 6; BE: −5.25 kcal/mol, Kd: 142.18 µM). The same binding profile was observed for withanolide A with respect to SARS-CoV-2 spike glycoprotein as compared to standard reference drugs arbidol (Table 7; BE: −3.14 kcal/mol, Kd: 4.99 mM) and hydroxychloroquine (Table 7; BE: −2.48 kcal/mol, Kd: 15.11 mM). Withanolide A also displayed a 1000× stronger binding to Nsp-10/Nsp-16 complex from SARS-CoV-2 in comparison to losartan (Table 11; BE: −6.49 kcal/mol, Kd: 17.54 µM) and hydroxychloroquine (Table 11; BE: −4.93 kcal/mol, Kd: 244.14 µM)\nWithanone also displayed significant binding to SARS-Cov-2 main protease (Table 10; BE: −6.14 kcal/mol, Kd: 31.77 µM) in comparison to standard reference drug oberadilol (Table 10; BE: −2.23 kcal/mol, Kd: 23.18 mM). The best docking poses of the WS phytoconstituents with respect to the human ACE2 receptor and viral target proteins have been depicted in Table 12 (Tables 12.1–12.7). Binding studies on WS constituents to unbound spike receptor-binding domain (RBD) of SARS-CoV-2 (PDB ID: 6M0J) and binding of WS phytoconstituents with SARS-CoV-2 spike receptor-binding domain (RBD) bound with ACE2 have been provided as supplementary data files ST1, SFI, ST2 and SF2, respectively.\nTable 12. Best docking poses of human and viral target proteins with selected WS phytoconstituents.\nLigands AutoDock v4.2.6 AutoDock vina iGEMDOCK v2.1\n12.1. Best docking poses of WS phytoconstituents with human ACE2 receptor (PDB ID: 1O8A) in comparison to the FDA approved standard reference drugs (Arbidol and Losartan)\nWithaferin A\nWithanolide A\nWithanolide B\nWithanolide D\nWithanolide E\nWithanone\nViscosalactone B\nAnaferine\nWithasomnine\nArbidol\nLosartan\n12.2. Best docking poses of WS phytoconstituents with SARS-CoV spike glycoprotein (PDB ID: 5WRG) in comparison to the FDA approved standard reference drugs (Arbidol and Hydroxychloroquine)\nWithaferin A\nWithanolide A\nWithanolide B\nWithanolide D\nWithanolide E\nWithanone\nViscosalactone B\nAnaferine\nWithasomnine\nArbidol\nHydroxychloroquine\n12.3. Best docking poses of WS phytoconstituents with SARS-CoV-2 spike glycoprotein (PDB ID: 6VXX) in comparison to FDA approved standard reference drugs (Arbidol and Hydroxychloroquine)\nWithaferin A\nWithanolide A\nWithanolide B\nWithanolide D\nWithanolide E\nWithanone\nViscosalactone B\nAnaferine\nWithasomnine\nArbidol\nHydroxychloroquine\n12.4. Best docking poses of WS phytoconstituents with papain like protease of SARS-CoV-2 (PDB ID: 6W9C) in comparison to the FDA approved standard reference drugs (Procainamide and Cinacalcet)\nWithaferin A\nWithanolide A\nWithanolide B\nWithanolide D\nWithanolide E\nWithanone\nViscosalactone B\nAnaferine\nWithasomnine\nProcainamide\nCinacalcet\n12.5. Best docking poses of WS phytoconstituents with SARS-CoV main protease/3CL-pro (PBB ID: 1P9U) in comparison to the FDA approved standard reference drugs (Oberadilol and Poziotinib)\nWithaferin A\nWithanolide A\nWithanolide B\nWithanolide D\nWithanolide E\nWithanone\nViscosalactone B\nAnaferine\nWithasomnine\nOberadilol\nPoziotinib\n12.6. Best docking poses of WS phytoconstituents with SARS-CoV-2 main protease/3CL-pro (PDB ID: 6LU7) in comparison to the FDA approved standard reference drugs (Oberadilol and Poziotinib)\nWithaferin A\nWithanolide A\nWithanolide B\nWithanolide D\nWithanolide E\nWithanone\nViscosalactone B\nAnaferine\nWithasomnine\nOberadilol\nPoziotinib\n12.7. Best docking poses of WS phytoconstituents with Nsp-10/Nsp-16 complex from SARS-CoV-2 (PDB ID: 6W75) in comparison to the FDA approved standard reference drugs (Losartan and Hydroxychloroquine)\nWithaferin A\nWithanolide A\nWithanolide B\nWithanolide D\nWithanolide E\nWithanone\nViscosalactone B\nAnaferine\nWithasomnine\nLosartan\nHydroxychloroquine\n\n3.4. Bioavailability radar and score as parameters for analysis of pharmacokinetic properties of WS phytoconstituents\nPharmacokinetics and pharmacodynamics are two interlinked terms in drug development having a mutual influence on each other. Bioavailability radar offers a first glimpse into the pharmaceutical properties of a prospective drug candidate. By convention, the pink area represents the optimal biological range for each physiochemical property including lipophilicity (XLOGP3 range 0.7–5.0), size (MW range 150–500), polarity (TPSA range 20–130 Å2), solubility (log S ≤ 6), saturation (fraction of carbons in sp3 hybridization ≤0.25), and flexibility (≤9). The Abbot Bioavailability Score62 is identical, but attempts to determine whether a compound is likely to have oral bioavailability score of at least 10% in rats and/or Caco-2 permeability (Martin, 2005). As is evident from Figure 2A and B, all withanolides from WS exhibited a significant bioavailability radar and score as comparable to the standard reference FDA-approved drugs.\nFigure 2. (A) Bioavailability radar and score prediction of WS phytoconstituents using SwissADME. (B) Bioavailability radar and score prediction of FDA–approved reference standard drugs using SwissADME.\n\n3.5. Druglikeness and Bioactivity score (BAS) analysis\nBiological targets of prospective drug candidates can be classified into ion channels, proteases, kinases, G-protein coupled receptors (GPCRs), nuclear receptors and enzymes. The BAS of WS phytoconstituents was determined using web-based software Molinspiration (www.molinspiration.com). As a general rule, it is known that if the BAS \u003e 0.0, then the drug candidate is physiologically active; if it is in the range −5.0 to 0.0; then the drug candidate is moderately active, and if the BAS\u003c −5.0, then the drug candidate is inactive.\nIt is evident from Table 13, that most of the WS phytoconstituents had positive values with respect to the following receptors.\n\n3.5.1. As GPCR ligands\nAll WS phytoconstituents wer"}

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67.23 nM), SARS-CoV-2 spike glycoprotein (Table 7; BE: −7.18 kcal/mol, Kd: 5.48 µM), SARS-CoV 3CL-pro main protease (Table 9; BE: –8.93 kcal/mol, Kd: 285.01 nM) and SARS-CoV-2 Nsp10/Nsp-16 complex (Table 11; BE: −10.38 kcal/mol, Kd: 24.67 nM). Interestingly, withanolide A exhibited almost 1000× times stronger binding to SARS-CoV main protease as compared to standard reference drugs arbidol (Table 6; BE: −4.91 kcal/mol, Kd: 251.65 µM) and hydroxychloroquine (Table 6; BE: −5.25 kcal/mol, Kd: 142.18 µM). The same binding profile was observed for withanolide A with respect to SARS-CoV-2 spike glycoprotein as compared to standard reference drugs arbidol (Table 7; BE: −3.14 kcal/mol, Kd: 4.99 mM) and hydroxychloroquine (Table 7; BE: −2.48 kcal/mol, Kd: 15.11 mM). Withanolide A also displayed a 1000× stronger binding to Nsp-10/Nsp-16 complex from SARS-CoV-2 in comparison to losartan (Table 11; BE: −6.49 kcal/mol, Kd: 17.54 µM) and hydroxychloroquine (Table 11; BE: −4.93 kcal/mol, Kd: 244.14 µM)\nWithanone also displayed significant binding to SARS-Cov-2 main protease (Table 10; BE: −6.14 kcal/mol, Kd: 31.77 µM) in comparison to standard reference drug oberadilol (Table 10; BE: −2.23 kcal/mol, Kd: 23.18 mM). The best docking poses of the WS phytoconstituents with respect to the human ACE2 receptor and viral target proteins have been depicted in Table 12 (Tables 12.1–12.7). Binding studies on WS constituents to unbound spike receptor-binding domain (RBD) of SARS-CoV-2 (PDB ID: 6M0J) and binding of WS phytoconstituents with SARS-CoV-2 spike receptor-binding domain (RBD) bound with ACE2 have been provided as supplementary data files ST1, SFI, ST2 and SF2, respectively.\nTable 12. Best docking poses of human and viral target proteins with selected WS phytoconstituents.\nLigands AutoDock v4.2.6 AutoDock vina iGEMDOCK v2.1\n12.1. Best docking poses of WS phytoconstituents with human ACE2 receptor (PDB ID: 1O8A) in comparison to the FDA approved standard reference drugs (Arbidol and Losartan)\nWithaferin A\nWithanolide A\nWithanolide B\nWithanolide D\nWithanolide E\nWithanone\nViscosalactone B\nAnaferine\nWithasomnine\nArbidol\nLosartan\n12.2. Best docking poses of WS phytoconstituents with SARS-CoV spike glycoprotein (PDB ID: 5WRG) in comparison to the FDA approved standard reference drugs (Arbidol and Hydroxychloroquine)\nWithaferin A\nWithanolide A\nWithanolide B\nWithanolide D\nWithanolide E\nWithanone\nViscosalactone B\nAnaferine\nWithasomnine\nArbidol\nHydroxychloroquine\n12.3. Best docking poses of WS phytoconstituents with SARS-CoV-2 spike glycoprotein (PDB ID: 6VXX) in comparison to FDA approved standard reference drugs (Arbidol and Hydroxychloroquine)\nWithaferin A\nWithanolide A\nWithanolide B\nWithanolide D\nWithanolide E\nWithanone\nViscosalactone B\nAnaferine\nWithasomnine\nArbidol\nHydroxychloroquine\n12.4. Best docking poses of WS phytoconstituents with papain like protease of SARS-CoV-2 (PDB ID: 6W9C) in comparison to the FDA approved standard reference drugs (Procainamide and Cinacalcet)\nWithaferin A\nWithanolide A\nWithanolide B\nWithanolide D\nWithanolide E\nWithanone\nViscosalactone B\nAnaferine\nWithasomnine\nProcainamide\nCinacalcet\n12.5. Best docking poses of WS phytoconstituents with SARS-CoV main protease/3CL-pro (PBB ID: 1P9U) in comparison to the FDA approved standard reference drugs (Oberadilol and Poziotinib)\nWithaferin A\nWithanolide A\nWithanolide B\nWithanolide D\nWithanolide E\nWithanone\nViscosalactone B\nAnaferine\nWithasomnine\nOberadilol\nPoziotinib\n12.6. Best docking poses of WS phytoconstituents with SARS-CoV-2 main protease/3CL-pro (PDB ID: 6LU7) in comparison to the FDA approved standard reference drugs (Oberadilol and Poziotinib)\nWithaferin A\nWithanolide A\nWithanolide B\nWithanolide D\nWithanolide E\nWithanone\nViscosalactone B\nAnaferine\nWithasomnine\nOberadilol\nPoziotinib\n12.7. Best docking poses of WS phytoconstituents with Nsp-10/Nsp-16 complex from SARS-CoV-2 (PDB ID: 6W75) in comparison to the FDA approved standard reference drugs (Losartan and Hydroxychloroquine)\nWithaferin A\nWithanolide A\nWithanolide B\nWithanolide D\nWithanolide E\nWithanone\nViscosalactone B\nAnaferine\nWithasomnine\nLosartan\nHydroxychloroquine\n\n3.4. Bioavailability radar and score as parameters for analysis of pharmacokinetic properties of WS phytoconstituents\nPharmacokinetics and pharmacodynamics are two interlinked terms in drug development having a mutual influence on each other. Bioavailability radar offers a first glimpse into the pharmaceutical properties of a prospective drug candidate. By convention, the pink area represents the optimal biological range for each physiochemical property including lipophilicity (XLOGP3 range 0.7–5.0), size (MW range 150–500), polarity (TPSA range 20–130 Å2), solubility (log S ≤ 6), saturation (fraction of carbons in sp3 hybridization ≤0.25), and flexibility (≤9). The Abbot Bioavailability Score62 is identical, but attempts to determine whether a compound is likely to have oral bioavailability score of at least 10% in rats and/or Caco-2 permeability (Martin, 2005). As is evident from Figure 2A and B, all withanolides from WS exhibited a significant bioavailability radar and score as comparable to the standard reference FDA-approved drugs.\nFigure 2. (A) Bioavailability radar and score prediction of WS phytoconstituents using SwissADME. (B) Bioavailability radar and score prediction of FDA–approved reference standard drugs using SwissADME.\n\n3.5. Druglikeness and Bioactivity score (BAS) analysis\nBiological targets of prospective drug candidates can be classified into ion channels, proteases, kinases, G-protein coupled receptors (GPCRs), nuclear receptors and enzymes. The BAS of WS phytoconstituents was determined using web-based software Molinspiration (www.molinspiration.com). As a general rule, it is known that if the BAS \u003e 0.0, then the drug candidate is physiologically active; if it is in the range −5.0 to 0.0; then the drug candidate is moderately active, and if the BAS\u003c −5.0, then the drug candidate is inactive.\nIt is evident from Table 13, that most of the WS phytoconstituents had positive values with respect to the following receptors.\n\n3.5.1. As GPCR ligands\nAll WS phytoconstituents wer"}