Table 2.
Ligand ADMET properties using pkCSM webserver
| ADMET | LIGANDS | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Type | Properties | A | B | C | D | E | F | G | H | I |
| Absorption | Water solubility (log mol/L) | -5.421 | -3.666 | -3.161 | -3.169 | -4.286 | -2.899 | -4.874 | -5.049 | -4.837 |
| Caco-2 permeability (log Papp in 10 cm/s) | 0.547 | 0.751 | 1.71 | 0.883 | 1.014 | 0.121 | 1.446 | 1.407 | 1.009 | |
| Intestinal absorption (human) (% Absorbed) | 92.836 | 91.032 | 97.599 | 86.587 | 89.765 | 84.897 | 85.961 | 95.756 | 90.906 | |
| Skin Permeability (log Kp) | -2.763 | -2.798 | -3.278 | -2.735 | -2.735 | -2.735 | -2.96 | -2.737 | -2.73 | |
| P-glycoprotein substrate | Yes | Yes | No | Yes | Yes | Yes | Yes | Yes | Yes | |
| P-glycoprotein I inhibitor | Yes | Yes | No | No | Yes | Yes | Yes | No | Yes | |
| P-glycoprotein II inhibitor | Yes | Yes | No | No | Yes | Yes | Yes | No | Yes | |
| Distribution | VDss (human) (log L/kg) | 0.931 | 1.596 | 0.291 | 1.738 | 0.529 | 0.616 | 0.83 | 0.072 | 2.223 |
| Fraction unbound (human) | 0.025 | 0.204 | 0.45 | 0.423 | 0 | 0.185 | 0.193 | 0.136 | 0.041 | |
| BBB permeability (log BB) | -0.647 | -0.394 | 0.444 | -0.738 | 0.222 | 0.004 | 0.488 | 0.414 | 0.847 | |
| CNS permeability (log PS) | -2.484 | -2.067 | -3.007 | -2.519 | -1.342 | 0.487 | -2.675 | -1.209 | -1.541 | |
| Metabolism | CYP2D6 substrate | No | Yes | No | No | Yes | No | No | No | Yes |
| CYP3A4 substrate | Yes | Yes | No | Yes | Yes | Yes | Yes | Yes | Yes | |
| CYP1A2 inhibitor | No | No | No | No | Yes | Yes | Yes | Yes | Yes | |
| CYP2C19 inhibitor | No | Yes | No | No | Yes | No | No | Yes | Yes | |
| CYP2C9 inhibitor | No | No | No | No | No | Yes | No | No | No | |
| CYP2D6 inhibitor | Yes | Yes | No | Yes | Yes | Yes | No | No | Yes | |
| CYP3A4 inhibitor | Yes | No | No | No | No | Yes | No | Yes | Yes | |
| Excretion | Total Clearance (log ml/min/kg) | 1.072 | 0.993 | 1.162 | 1.132 | 0.718 | 0.631 | 0.43 | 0.535 | 0.385 |
| Renal OCT2 substrate | Yes | No | Yes | No | No | Yes | Yes | No | No | |
| Toxicity | AMES toxicity | No | No | Yes | No | No | Yes | No | Yes | No |
|
Max. tolerated dose (human) (log mg/kg/day) |
-0.181 | -0.019 | 0.306 | 0.105 | 0.41 | 0.107 | -0.283 | 0.288 | 0.104 | |
| hERG I inhibitor | No | No | No | No | Yes | Yes | No | No | No | |
| hERG II inhibitor | Yes | Yes | No | Yes | Yes | Yes | Yes | No | Yes | |
| Oral Rat Acute Toxicity (LD50) (mol/kg) | 2.973 | 2.793 | 2.096 | 2.951 | 2.252 | 2.442 | 2.926 | 2.236 | 2.751 | |
|
Oral Rat Chronic Toxicity (LOAEL) (log mg/kg_bw/day) |
1.309 | 0.674 | 1.592 | 1.101 | 1.063 | 1.088 | 0.473 | 1.506 | 0.851 | |
| Hepatotoxicity | No | No | No | Yes | No | Yes | Yes | No | Yes | |
| Skin Sensitisation | No | No | Yes | No | No | No | No | No | No | |
| T. Pyriformis toxicity (log ug/L) | 0.667 | 0.327 | 0.46 | 0.305 | 0.287 | 0.285 | 1.186 | 0.489 | 1.057 | |
| Minnow toxicity (log mM) | -1.947 | -0.825 | 1.582 | 2.009 | 0.379 | 2.339 | 0.913 | -1.289 | 4.016 | |
Legend: A: Dexverapamil. B: Emetine. C: Parthenolide. D: Dobutamine. E: Terfenadine. F: Pimozide. G: Mefloquine. H: Ellipticine. I: Trifluoperazine. Based on pkCSM ADMET predictive model [Ref: 24], a compound is said to have high Caco-2 permeability at a value of > 0.90; poor GIA at less than 30% absorption; low skin permeability (logKp > -2.5); VDss is low at < 0.71 L/kg (log VDss < -0.15) and high at > 2.81 L/kg (log VDss > 0.45); BBB permeant at a logBB > 0.33 and non-permeant at logBB < -1; CNS permeant at a logPS > -2 and non-permeant at a logPS < -3; Tetrahymena pyriformis toxicity (pIGC50) at a value > − 0.5 log µg/L is considered toxic; minnow toxicity (LC50) at a value < 0.5 mM (logLC50 < -0.3) is regarded as high acute toxicity; maximum recommended tolerated doses (MRTD) of ≤ 0.477 log(mg/kg/day) is considered low, and high if > 0.477 log(mg/kg/day)