Using In Silico Approach for Metabolomic and Toxicity Prediction of Alternariol
Abstract
:1. Introduction
2. Results
2.1. Metabolomics Profile of Alternariol
2.2. Physicochemical Properties, Pharmacokinetic Predictions and Drug Likeness
2.3. Prediction of Toxicity
3. Discussion
4. Conclusions
5. Materials and Methods
5.1. Prediction of Alternariol Metabolites
5.2. Prediction of Physicochemical Properties, Pharmacokinetic Predictions and Drug Likeness
5.3. Prediction of Toxicity
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Parent Compound/Metabolite | Canonical SMILES |
---|---|
Alternariol (AOH) | CC1=CC(O)=CC2=C1C1=CC(O)=CC(O)=C1C(=O)O2 |
Aromatic Hydroxylation | |
Metabolite (M1) | CC1=CC(O)=CC2=C1C1=CC(O)=C(O)C(O)=C1C(=O)O2 |
Metabolite (M2) | CC1=CC(O)=C(O)C2=C1C1=CC(O)=CC(O)=C1C(=O)O2 |
Metabolite (M3) | CC1=CC(O)=CC2=C1C1=C(O)C(O)=CC(O)=C1C(=O)O2 |
O-Glucuronidation | |
Metabolite (M4) | CC1=CC(O)=CC2=C1C1=CC(O)=CC(OC3OC(C(O)C(O)C3O)C(O)=O)=C1C(=O)O2 |
Metabolite (M5) | CC1=CC(O)=CC2=C1C1=CC(OC3OC(C(O)C(O)C3O)C(O)=O)=CC(O)=C1C(=O)O2 |
Metabolite (M6) | CC1=CC(OC2OC(C(O)C(O)C2O)C(O)=O)=CC2=C1C1=CC(O)=CC(O)=C1C(=O)O2 |
O-Sulfation | |
Metabolite (M7) | CC1=CC(OS(O)(=O)=O)=CC2=C1C1=CC(O)=CC(O)=C1C(=O)O2 |
Metabolite (M8) | CC1=CC(O)=CC2=C1C1=CC(OS(O)(=O)=O)=CC(O)=C1C(=O)O2 |
Metabolite (M9) | CC1=CC(O)=CC2=C1C1=CC(O)=CC(OS(O)(=O)=O)=C1C(=O)O2 |
Methylation | |
Metabolite (M10) | COC1=CC(O)=C2C(=O)OC3=CC(O)=CC(C)=C3C2=C1 |
Metabolite (M11) | COC1=CC(C)=C2C(OC(=O)C3=C(O)C=C(O)C=C23)=C1 |
Metabolite (M12) | COC1=CC(O)=CC2=C1C(=O)OC1=CC(O)=CC(C)=C21 |
Parent Compound/Metabolite | MW (g/mol) (≤500) | HBA (≤10) | HBD (≤5) | cLogP (<5) | MR (40–130) | n-ROTB | TPSA (Å2) |
---|---|---|---|---|---|---|---|
Alternariol (AOH) | 258.23 | 5 | 3 | 71.03 | 0 | 90.9 | |
Aromatic Hydroxylation | |||||||
Metabolite (M1) | 274.23 | 6 | 4 | 1.71 | 73.05 | 0 | 111.1 |
Metabolite (M2) | 1.72 | ||||||
Metabolite (M3) | 1.46 | ||||||
O-Glucuronidation | |||||||
Metabolite (M4) | 434.35 | 11 * | 6 * | 0.06 | 103.79 | 3 | 187.1 |
Metabolite (M5) | 0.31 | ||||||
Metabolite (M6) | 0.31 | ||||||
O-Sulfation | |||||||
Metabolite (M7) | 338.29 | 8 | 3 | 1.58 | 81.22 | 3 | 142.6 |
Metabolite (M8) | 1.57 | ||||||
Metabolite (M9) | 1.38 | ||||||
Methylation | |||||||
Metabolite (M10) | 272.25 | 5 | 2 | 2.55 | 75.49 | 1 | 79.9 |
Metabolite (M11) | 2.55 | ||||||
Metabolite (M12) | 2.55 |
Model Name/Parameters | AOH | Aromatic Hydroxilation | O-Glucuronidation | O-Sulfation | Methylation | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
M1 | M2 | M3 | M4 | M5 | M6 | M7 | M8 | M9 | M10 | M11 | M12 | ||
Absorption | |||||||||||||
Water solubility (log mol/L) | −2.982 | −3.059 | −3.151 | −3.072 | −2.892 | −2.894 | −2.894 | −3.158 | −3.118 | −2.938 | −3.5 | −3.293 | −3.388 |
Caco2 permeability (log Paap in 10−6 cm/s) | 1.025 | 0.838 | 0.815 | 0.818 | −0.745 | −0.699 | −0.885 | 0.388 | 0.635 | 0.717 | 1.057 | 0.952 | 0.9 |
Intestinal absorption (human) % | 95.473 | 73.662 | 81.84 | 76.718 | 18.049 | 18.043 | 14.941 | 45.397 | 48.67 | 47.87 | 95.627 | 95.804 | 97.087 |
Skin Permeability (log Kp) | −2.745 | −2.735 | −2.735 | −2.735 | −2.735 | −2.735 | −2.735 | −2.735 | −2.735 | −2.735 | −2.739 | −2.737 | −2.747 |
P-glycoprotein substrate | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
P-glycoprotein I inhibitor | No | No | No | No | No | No | No | No | No | No | No | No | No |
P-glycoprotein II inhibitor | No | No | No | No | No | No | No | No | No | No | No | No | No |
Distribution | |||||||||||||
VDss (human) (log L/kg) | −0.032 | 0.064 | 0.144 | 0.215 | −0.891 | −0.928 | −1.032 | −0.557 | −0.306 | −0.402 | −0.009 | −0.061 | 0.208 |
Fraction unbound (human) (Fu) | 0.14 | 0.083 | 0.11 | 0.112 | 0.22 | 0.202 | 0.193 | 0.163 | 0.176 | 0.223 | 0.125 | 0.164 | 0.164 |
BBB permeability (log BB) | −0.965 | −1.32 | −1.218 | −1.325 | −1.736 | −1.647 | −1.834 | −1.556 | −1.397 | −1.48 | −0.107 | −0.225 | −0.16 |
CNS permeability (log PS) | −2.247 | −2.557 | −2.499 | −2.498 | −4.452 | −4.438 | −4.551 | −3.76 | −3.565 | −3.5 | −2.236 | −2.24 | −2.218 |
Metabolism | |||||||||||||
CYP2D6 substrate | No | No | No | No | No | No | No | No | No | No | No | No | No |
CYP3A4 substrate | No | No | No | No | No | No | No | No | No | No | No | No | No |
CYP1A2 inhibitor | Yes | Yes | Yes | Yes | No | No | No | Yes | Yes | No | Yes | Yes | Yes |
CYP2C19 inhibitor | No | No | No | No | No | No | No | No | No | No | Yes | Yes | Yes |
CYP2C9 inhibitor | Yes | Yes | No | No | No | No | No | No | No | No | No | Yes | Yes |
CYP2D6 inhibitor | No | No | No | No | No | No | No | No | No | No | No | No | No |
CYP3A4 inhibitor | No | No | No | No | No | No | No | No | No | No | No | No | No |
Excretion | |||||||||||||
Total Clearance (log mL/min/kg) | 0.723 | 0.658 | 0.676 | 0.717 | 0.77 | 0.785 | 0.815 | 0.841 | 0.848 | 0.831 | 0.841 | 0.82 | 0.79 |
Renal OCT2 substrate | No | No | No | No | No | No | No | No | No | No | No | No | No |
Toxicity | AOH | Reaction/Metabolites | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Aromatic Hydroxilation | O-Glucuronidation | O-Sulfation | Methylation | ||||||||||
M1 | M2 | M3 | M4 | M5 | M6 | M7 | M8 | M9 | M10 | M11 | M12 | ||
AMES toxicity | Yes | Yes | No | Yes | No | No | No | No | No | No | No | Yes | No |
Max. tolerated dose (human) | 0.697 | 0.94 | 0.832 | 0.888 | 0.681 | 0.693 | 0.654 | 0.976 | 0.945 | 0.918 | 0.489 | 0.765 | 0.472 |
Oral Rat Acute Toxicity (LD50) | 2.82 | 2.611 | 2.515 | 2.586 | 2.438 | 2.441 | 2.466 | 2.582 | 2.63 | 2.509 | 2.918 | 3.001 | 3.036 |
Oral Rat Chronic Toxicity (LOAEL) | 1.51 | 2.747 | 2.675 | 2.625 | 4.409 | 4.101 | 3.945 | 1.917 | 2.169 | 2.158 | 1.285 | 0.98 | 0.944 |
T. pyriformis toxicity | 0.335 | 0.301 | 0.305 | 0.297 | 0.285 | 0.285 | 0.285 | 0.285 | 0.285 | 0.285 | 0.339 | 0.349 | 0.348 |
Minnow toxicity | 1.512 | 1.235 | 1.54 | 2.128 | 3.918 | 3.476 | 4.205 | 0.414 | 1.586 | 1.927 | 0.332 | −0.352 | 0.319 |
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Marin, D.E.; Taranu, I. Using In Silico Approach for Metabolomic and Toxicity Prediction of Alternariol. Toxins 2023, 15, 421. https://doi.org/10.3390/toxins15070421
Marin DE, Taranu I. Using In Silico Approach for Metabolomic and Toxicity Prediction of Alternariol. Toxins. 2023; 15(7):421. https://doi.org/10.3390/toxins15070421
Chicago/Turabian StyleMarin, Daniela Eliza, and Ionelia Taranu. 2023. "Using In Silico Approach for Metabolomic and Toxicity Prediction of Alternariol" Toxins 15, no. 7: 421. https://doi.org/10.3390/toxins15070421