Table 7 Pharmacokinetic features for compound F9.
Property | Value | Comment | |
|---|---|---|---|
Physicochemical Property | |||
Molecular Weight | 563.24 | Contain hydrogen atoms. Optimal: 100–600 | |
Volume | 560.792 | Van der Waals volume | |
Density | 1.004 | Density = MW / Volume | |
nHA | 12 | Number of hydrogen bond acceptors. Optimal: 0–12 | |
nHD | 5 | Number of hydrogen bond donors. Optimal: 0–7 | |
nRot | 7 | Number of rotatable bonds. Optimal: 0–11 | |
nRing | 4 | Number of rings. Optimal: 0–6 | |
MaxRing | 17 | Number of atoms in the biggest ring. Optimal: 0–18 | |
nHet | 12 | Number of heteroatoms. Optimal: 1–15 | |
fChar | 0 | Formal charge. Optimal: − 4 to 4 | |
nRig | 35 | Number of rigid bonds. Optimal: 0–30 | |
Flexibility | 0.2 | Flexibility = nRot /nRig | |
Stereo Centers | 3 | Optimal: ≤ 2 | |
TPSA | 177.0 | Topological Polar Surface Area. Optimal: 0–140 | |
logS | -3.046 | Log of the aqueous solubility. Optimal: -4 ~ 0.5 log mol/L | |
logP | 0.832 | Log of the octanol/water partition coefficient. Optimal: 0–3 | |
logD | 0.792 | logP at physiological pH 7.4. Optimal: 1–3 | |
Property | Value | Decision | Comment |
|---|---|---|---|
Medicinal Chemistry | |||
QED | 0.213 |
| A measure of drug-likeness based on the concept of desirability Attractive: > 0.67; unattractive: 0.49–0.67; too complex: < 0.34 |
SAscore | 5.094 |
| Synthetic accessibility score is designed to estimate ease of synthesis of drug-like molecules SAscore ≥ 6, difficult to synthesize; SAscore < 6, easy to synthesize |
Fsp3 | 0.379 |
| The number of sp3 hybridized carbons / total carbon count, correlating with melting point and solubility Fsp3 ≥0.42 is considered a suitable value |
MCE-18 | 85.8 |
| MCE-18 stands for medicinal chemistry evolution MCE-18 ≥ 45 is considered a suitable value |
Absorption | |||
Caco-2 Permeability | -6.443 |
| Optimal: higher than -5.15 Log unit |
MDCK Permeability | 5.5e-05 |
| Low permeability: < 2 × 10−6 cm/s Medium permeability: 2–20 × 10−6 cm/s High passive permeability: > 20 × 10−6 cm/s |
Pgp-inhibitor | 0.078 |
| Category 1: Inhibitor; Category 0: Non-inhibitor The output value is the probability of being Pgp-inhibitor |
Pgp-substrate | 0.965 |
| Category 1: substrate; Category 0: Non-substrate The output value is the probability of being Pgp-substrate |
HIA | 0.536 |
| Human Intestinal Absorption Category 1: HIA + ( HIA < 30%); Category 0: HIA-( HIA < 30%) The output value is the probability of being HIA+ |
F20% | 0.993 |
| 20% Bioavailability Category 1: F20% + (bioavailability < 20%); Category 0: F20%- (bioavailability ≥ 20%) The output value is the probability of being F20% + |
NPscore | 0.814 | – | Natural product-likeness score This score is typically in the range from − 5 to 5. The higher the score is, the higher the probability is that the molecule is a NP |
Lipinski Rule | Rejected |
| MW ≤ 500; logP ≤ 5; Hacc ≤ 10; Hdon ≤ 5 If two properties are out of range, a poor absorption or permeability is possible, one is acceptable |
Pfizer Rule | Accepted |
| logP > 3; TPSA < 75 Compounds with a high log P (> 3) and low TPSA (< 75) are likely to be toxic |
GSK Rule | Rejected |
| MW ≤ 400; logP ≤ 4 Compounds satisfying the GSK rule may have a more favorable ADMET profile |
Golden Triangle | Rejected |
| 200 ≤ MW ≤ 50; -2 ≤ logD ≤ 5 Compounds satisfying the Golden Triangle rule may have a more favorable ADMET profile |
PAINS | 0 alerts | – | Pan Assay Interference Compounds, frequent hitters, Alpha-screen artifacts and reactive compound |
ALARM NMR | 1 alerts | – | Thiol reactive compounds |
BMS | 0 alerts | – | Undesirable, reactive compounds |
Chelator Rule | 0 alerts | – | Chelating compounds |
F30% | 0.996 |
| 30% Bioavailability Category 1: F30% + (bioavailability < 30%); Category 0: F30%- (bioavailability ≥ 30%) The output value is the probability of being F30% + |
Distribution | |||
PPB | 27.15% |
| Plasma Protein Binding Optimal: < 90%. Drugs with high protein-bound may have a low therapeutic index |
VD | 0.298 |
| Volume Distribution Optimal: 0.04-20L/kg |
BBB Penetration | 0.471 |
| Blood–Brain Barrier Penetration Category 1: BBB+; Category 0: BBB− The output value is the probability of being BBB+ |
Fu | 69.47% |
| The fraction unbound in plasms Low: < 5%; Middle: 5–20%; High: > 20% |
Property | Value | Comment | |
|---|---|---|---|
Metabolism | |||
CYP1A2 inhibitor | 0.009 | Category 1: Inhibitor; Category 0: Non-inhibitor The output value is the probability of being inhibitor | |
CYP1A2 substrate | 0.064 | Category 1: Substrate; Category 0: Non-substrate The output value is the probability of being substrate | |
CYP2C19 inhibitor | 0.156 | Category 1: Inhibitor; Category 0: Non-inhibitor The output value is the probability of being inhibitor | |
CYP2C19 substrate | 0.05 | Category 1: Substrate; Category 0: Non-substrate The output value is the probability of being substrate | |
CYP2C9 inhibitor | 0.402 | Category 1: Inhibitor; Category 0: Non-inhibitor The output value is the probability of being inhibitor | |
CYP2C9 substrate | 0.072 | Category 1: Substrate; Category 0: Non-substrate The output value is the probability of being substrate | |
CYP2D6 inhibitor | 0.012 | Category 1: Inhibitor; Category 0: Non-inhibitor The output value is the probability of being inhibitor | |
CYP2D6 substrate | 0.173 | Category 1: Substrate; Category 0: Non-substrate The output value is the probability of being substrate | |
CYP3A4 inhibitor | 0.898 | Category 1: Inhibitor; Category 0: Non-inhibitor The output value is the probability of being inhibitor | |
CYP3A4 substrate | 0.22 | Category 1: Substrate; Category 0: Non-substrate The output value is the probability of being substrate | |
Property | Value | Decision | Comment |
|---|---|---|---|
Excretion | |||
CL | 3.447 |
| Clearance High: > 15 mL/min/kg; moderate: 5–15 mL/min/kg; low: < 5 mL/min/kg |
T1/2 | 0.633 | – | Category 1: long half-life; Category 0: short half-life long half-life: > 3 h; short half-life: < 3 h The output value is the probability of having long half-life |
Toxicity | |||
hERG Blockers | 0.087 |
| Category 1: active; Category 0: inactive The output value is the probability of being active |
H-HT | 0.414 |
| Human Hepatotoxicity Category 1: H-HT positive( +); Category 0: H-HT negative(-) The output value is the probability of being toxic |
DILI | 0.51 |
| Drug Induced Liver Injury Category 1: drugs with a high risk of DILI; Category 0: drugs with no risk of DILI. The output value is the probability of being toxic |
AMES Toxicity | 0.018 |
| Category 1: Ames positive( +); Category 0: Ames negative(-) The output value is the probability of being toxic |
Rat Oral Acute Toxicity | 0.453 |
| Category 0: low-toxicity; Category 1: high-toxicity The output value is the probability of being highly toxic |
FDAMDD | 0.931 |
| Maximum Recommended Daily Dose Category 1: FDAMDD ( +); Category 0: FDAMDD (-) The output value is the probability of being positive |
Skin Sensiti zation | 0.215 |
| Category 1: Sensitizer; Category 0: Non-sensitizer The output value is the probability of being sensitizer |
Carcinogen city | 0.063 |
| Category 1: carcinogens; Category 0: non-carcinogens The output value is the probability of being toxic |
Eye Corrosion | 0.003 |
| Category 1: corrosives; Category 0: noncorrosives The output value is the probability of being corrosives |
Eye Irritation | 0.008 |
| Category 1: irritants; Category 0: nonirritants The output value is the probability of being irritants |
Respiratory Toxicity | 0.628 |
| Category 1: respiratory toxicants; Category 0: respiratory nontoxicants The output value is the probability of being toxic |
Property | Value | Comment | |
|---|---|---|---|
Environmental toxicity | |||
Bioconcentration Factors | 0.309 | Bioconcentration factors are used for considering secondary poisoning potential and assessing risks to human health via the food chain The unit is −log10[(mg/L)/(1000*MW)] | |
IGC50 | 2.999 | Tetrahymena pyriformis 50 percent growth inhibition concentration The unit is −log10[(mg/L)/(1000*MW)] | |
LC50FM | 3.901 | 96-h fathead minnow 50 percent lethal concentration The unit is −log10[(mg/L)/(1000*MW)] | |
LC50DM | 3.882 | 48-h daphnia magna 50 percent lethal concentration The unit is −log10[(mg/L)/(1000*MW)] | |
Property | Value | Decision | Comment |
|---|---|---|---|
Tox21 pathway | |||
NR-AR | 0.137 |
| Androgen receptor Category 1: actives; Category 0: inactives The output value is the probability of being active |
NR-AR-LBD | 0.227 |
| Androgen receptor ligand-binding domain Category 1: actives; Category 0: inactives The output value is the probability of being active |
NR-AhR | 0.021 |
| Aryl hydrocarbon receptor Category 1: actives; Category 0: inactives The output value is the probability of being active |
NR-Aromatase | 0.043 |
| Category 1: actives; Category 0: inactives The output value is the probability of being active |
NR-ER | 0.265 |
| Estrogen receptor Category 1: actives; Category 0: inactives The output value is the probability of being active |
NR-ER-LBD | 0.006 |
| Estrogen receptor ligand-binding domain Category 1: actives; Category 0: inactives The output value is the probability of being active |
NR-PPAR-gamma | 0.415 |
| Peroxisome proliferator-activated receptor gamma Category 1: actives; Category 0: inactives The output value is the probability of being active |
SR-ARE | 0.403 |
| Antioxidant response element Category 1: actives; Category 0: inactives The output value is the probability of being active |
SR-ATAD5 | 0.013 |
| ATPase family AAA domain-containing protein 5 Category 1: actives; Category 0: inactives The output value is the probability of being active |
SR-HSE | 0.023 |
| Heat shock factor response element Category 1: actives; Category 0: inactives The output value is the probability of being active |
SR-MMP | 0.309 |
| Mitochondrial membrane potential Category 1: actives; Category 0: inactives The output value is the probability of being active |
SR-p53 | 0.042 |
| Category 1: actives; Category 0: inactives The output value is the probability of being active |
Property | Value | Comment | |
|---|---|---|---|
Toxicophore Rules | |||
Acute Toxicity Rule | 0 alerts | 20 substructures acute toxicity during oral administration | |
Genotoxic Carcinogenicity Rule | 0 alerts | 117 substructures carcinogenicity or mutagenicity | |
NonGenotoxic Carcinogenicity Rule | 0 alerts | 23 substructures carcinogenicity through nongenotoxic mechanisms | |
Skin Sensitization Rule | 4 alerts | 155 substructures skin irritation | |
Aquatic Toxicity Rule | 0 alerts | 99 substructures toxicity to liquid(water) | |
NonBiodegradable Rule | 0 alerts | 19 substructures non-biodegradable | |
SureChEMBL Rule | 0 alerts | 164 substructures MedChem unfriendly status | |
