Table 4.
Physico-chemical properties, lipophilicity, solubility, pharmacokinetic, drug likeness and medicinal chemistry properties of the PI3K-α and PKC-η inhibitors.
| Leads | Physicochemical properties | Lipophilicity | Water solubility | Pharmacokinetics | Drug likeness | Medicinal chemistry |
|---|---|---|---|---|---|---|
| PI3K-α inhibitors | ||||||
| 1 |
Formula: C32H40ClN3O5 Molecular weight: 582.13 g/mol Num. heavy atoms: 41 Num. arom. heavy atoms: 15 Fraction Csp3: 0.53 Num. rotatable bonds: 5 Num. H-bond acceptors: 5 Num. H-bond donors: 3 Molar Refractivity: 168.83 TPSA: 98.40 Å2 |
Log Po/w (iLOGP): 4.47 Log Po/w (XLOGP3): 4.66 Log Po/w (WLOGP): 4.69 Log Po/w (MLOGP): 3.06 Log Po/w (SILICOS-IT): 3.93 Consensus Log Po/w : 4.16 |
Log S (ESOL): -6.33 Solubility: 2.75e-04 mg/ml ; 4.72e-07 mol/l Class: Poorly soluble Log S (Ali): -6.45 Solubility: 2.05e-04 mg/ml ; 3.52e-07 mol/l Class: Poorly soluble Log S (SILICOS-IT): -6.40 Solubility: 2.30e-04 mg/ml ; 3.94e-07 mol/l Class: Poorly soluble |
GI absorption: High BBB permeant: No P-gp substrate: No CYP1A2 inhibitor: No CYP2C19 inhibitor: No CYP2C9 inhibitor: No CYP2D6 inhibitor: No CYP3A4 inhibitor: No Log Kp (skin permeation): -6.54 cm/s |
Lipinski: Yes; 1 violation: MW > 500 Ghose: No; 3 violations: MW > 480, MR > 130, #atoms > 70 Veber: Yes Egan: Yes Muegge: Yes Bioavailability Score: 0.55 |
PAINS: 0 alert Brenk: 0 alert Leadlikeness: No; 2 violations: MW > 350, XLOGP3 > 3.5 Synthetic accessibility: 4.99 |
| 2 |
Formula: C27H35N3O4 Molecular weight: 465.58 g/mol Num. heavy atoms: 34 Num. arom. heavy atoms: 12 Fraction Csp3: 0.48 Num. rotatable bonds: 8 Num. H-bond acceptors: 6 Num. H-bond donors: 1 Molar Refractivity: 140.50 TPSA : 75.13 Å2 |
Log Po/w (iLOGP): 4.24 Log Po/w (XLOGP3): 3.47 Log Po/w (WLOGP): 2.85 Log Po/w (MLOGP): 1.56 Log Po/w (SILICOS-IT): 3.60 Consensus Log Po/w : 3.14 |
Log S (ESOL): -4.65 Solubility: 1.05e-02 mg/ml ; 2.26e-05 mol/l Class: Moderately soluble Log S (Ali): -4.73 Solubility: 8.67e-03 mg/ml ; 1.86e-05 mol/l Class: Moderately soluble Log S (SILICOS-IT): -5.75 Solubility: 8.30e-04 mg/ml ; 1.78e-06 mol/l Class: Moderately soluble |
GI absorption: High BBB permeant: Yes P-gp substrate: Yes CYP1A2 inhibitor: No CYP2C19 inhibitor: No CYP2C9 inhibitor: No CYP2D6 inhibitor: Yes CYP3A4 inhibitor: Yes Log Kp (skin permeation): -6.68 cm/s |
Lipinski: Yes; 0 violation Ghose: No; 1 violation: MR > 130 Veber: Yes Egan: Yes Muegge: Yes Bioavailability Score: 0.55 |
PAINS: 0 alert Brenk: 0 alert Leadlikeness: No; 2 violations: MW > 350, Rotors > 7 Synthetic accessibility: 4.14 |
| 3 |
Formula: C26H31N5O3 Molecular weight: 461.56 g/mol Num. heavy atoms: 34 Num. arom. heavy atoms: 17 Fraction Csp3: 0.42 Num. rotatable bonds: 7 Num. H-bond acceptors: 6 Num. H-bond donors: 1 Molar Refractivity: 136.27 TPSA : 83.72 Å2 |
Log Po/w (iLOGP): 2.88 Log Po/w (XLOGP3): 1.79 Log Po/w (WLOGP): 1.42 Log Po/w (MLOGP): 1.27 Log Po/w (SILICOS-IT): 2.61 Consensus Log Po/w : 1.99 |
Log S (ESOL): -3.74 Solubility: 8.45e-02 mg/ml ; 1.83e-04 mol/l Class: Soluble Log S (Ali): -3.17 Solubility: 3.14e-01 mg/ml ; 6.81e-04 mol/l Class: Soluble Log S (SILICOS-IT): -5.91 Solubility: 5.73e-04 mg/ml ; 1.24e-06 mol/l Class: Moderately soluble |
GI absorption: High BBB permeant: No P-gp substrate: Yes CYP1A2 inhibitor: No CYP2C19 inhibitor: No CYP2C9 inhibitor: Yes CYP2D6 inhibitor: Yes CYP3A4 inhibitor: Yes Log Kp (skin permeation): -7.84 cm/s |
Lipinski: Yes; 0 violation Ghose: No; 1 violation: MR > 130 Veber: Yes Egan: Yes Muegge: Yes Bioavailability Score: 0.55 |
PAINS: 0 alert Brenk : 0 alert Leadlikeness; No; 1 violation: MW > 350 Synthetic accessibility: 4.21 |
| Ppictilisilinib |
Formula: C23H27N7O3S2 Molecular weight: 513.64 g/mol Num. heavy atoms: 35 Num. arom. heavy atoms: 18 Fraction Csp3: 0.43 Num. rotatable bonds: 5 Num. H-bond acceptors: 8 Num. H-bond donors: 1 Molar Refractivity: 147.70 TPSA: 144.17 Å2 |
Log Po/w (iLOGP): 3.01 Log Po/w (XLOGP3): 1.62 Log Po/w (WLOGP): 1.93 Log Po/w (MLOGP): 0.94 Log Po/w (SILICOS-IT): 2.57 Consensus Log Po/w : 2.01 |
Log S (ESOL) : -4.10 Solubility: 4.12e-02 mg/ml ; 8.02e-05 mol/l Class : Moderately soluble Log S (Ali): -4.26 Solubility: 2.82e-02 mg/ml ; 5.50e-05 mol/l Class : Moderately soluble Log S (SILICOS-IT) : -6.12 Solubility: 3.91e-04 mg/ml ; 7.60e-07 mol/l Class : Poorly soluble |
GI absorption: Low BBB permeant : No P-gp substrate : Yes CYP1A2 inhibitor : No CYP2C19 inhibitor : Yes CYP2C9 inhibitor : Yes CYP2D6 inhibitor : Yes CYP3A4 inhibitor : Yes Log Kp (skin permeation) : -8.28 cm/s |
Lipinski: Yes; 1 violation: MW > 500 Ghose : No; 2 violations: MW > 480, MR > 130 Veber : No; 1 violation: TPSA > 140 Egan : No; 1 violation: TPSA > 131.6 Muegge : Yes Bioavailability Score : 0.55 |
PAINS : 0 alert Brenk : 0 alert Leadlikeness : No; 1 violation: MW > 350 Synthetic accessibility : 3.95 |
| PKC-η inhibitors | ||||||
| 1 |
Formula: C23H18N2O4S Molecular weight: 418.47 g/mol Num. heavy atoms: 30 Num. arom. heavy atoms: 21 Fraction Csp3: 0.13 Num. rotatable bonds: 3 Num. H-bond acceptors: 5 Num. H-bond donors: 2 Molar Refractivity: 119.78 TPSA : 111.13 Å2 |
Log Po/w (iLOGP) : 3.05 Log Po/w (XLOGP3) : 4.58 Log Po/w (WLOGP) : 3.88 Log Po/w (MLOGP) : 2.31 Log Po/w (SILICOS-IT) : 4.50 Consensus Log Po/w : 3.66 |
Log S (ESOL) : -5.64 Solubility: 9.59e-04 mg/ml ; 2.29e-06 mol/l Class : Moderately soluble Log S (Ali) : -6.64 Solubility: 9.64e-05 mg/ml ; 2.30e-07 mol/l Class : Poorly soluble Log S (SILICOS-IT) : -6.62 Solubility: 1.02e-04 mg/ml ; 2.43e-07 mol/l Class : Poorly soluble |
GI absorption : High BBB permeant : No P-gp substrate : No CYP1A2 inhibitor : No CYP2C19 inhibitor : Yes CYP2C9 inhibitor : Yes CYP2D6 inhibitor : No CYP3A4 inhibitor : Yes Log Kp (skin permeation) : -5.60 cm/s |
Lipinski : Yes; 0 violation Ghose : Yes Veber : Yes Egan : Yes Muegge : Yes Bioavailability Score : 0.55 |
PAINS : 0 alert Brenk : 0 alert Leadlikeness : No; 2 violations: MW > 350, XLOGP3 > 3.5 Synthetic accessibility : 3.30 |
| 2 |
Formula: C21H21N3O3S Molecular weight: 395.47 g/mol Num. heavy atoms: 28 Num. arom. heavy atoms: 15 Fraction Csp3: 0.33 Num. rotatable bonds: 3 Num. H-bond acceptors: 5 Num. H-bond donors: 2 Molar Refractivity: 112.91 TPSA : 116.92 Å2 |
Log Po/w (iLOGP) : 3.04 Log Po/w (XLOGP3) : 2.52 Log Po/w (WLOGP) : 2.74 Log Po/w (MLOGP) : 1.83 Log Po/w (SILICOS-IT) : 3.89 Consensus Log Po/w : 2.80 |
Log S (ESOL): -4.08 Solubility: 3.30e-02 mg/ml ; 8.36e-05 mol/l Class : Moderately soluble Log S (Ali): -4.62 Solubility: 9.45e-03 mg/ml ; 2.39e-05 mol/l Class : Moderately soluble Log S (SILICOS-IT) : -5.43 Solubility: 1.46e-03 mg/ml ; 3.70e-06 mol/l Class : Moderately soluble |
GI absorption: High BBB permeant : No P-gp substrate : Yes CYP1A2 inhibitor : Yes CYP2C19 inhibitor : Yes CYP2C9 inhibitor : Yes CYP2D6 inhibitor : Yes CYP3A4 inhibitor : Yes Log Kp (skin permeation) : -6.92 cm/s |
Lipinski : Yes; 0 violation Ghose : Yes Veber : Yes Egan : Yes Muegge : Yes Bioavailability Score : 0.55 |
PAINS : 0 alert Brenk : 0 alert Leadlikeness : No; 1 violation: MW > 350 Synthetic accessibility : 3.27 |
| 3 |
Formula: C22H20N2O5 Molecular weight: 392.40 g/mol Num. heavy atoms: 29 Num. arom. heavy atoms: 18 Fraction Csp3: 0.18 Num. rotatable bonds: 3 Num. H-bond acceptors: 6 Num. H-bond donors: 3 Molar Refractivity: 111.39 TPSA : 103.12 Å2 |
Log Po/w (iLOGP) : 1.90 Log Po/w (XLOGP3) : 3.36 Log Po/w (WLOGP) : 2.68 Log Po/w (MLOGP) : 1.58 Log Po/w (SILICOS-IT) : 2.90 Consensus Log Po/w : 2.48 |
Log S (ESOL) : -4.65 Solubility: 8.76e-03 mg/ml ; 2.23e-05 mol/l Class : Moderately soluble Log S (Ali) : -5.20 Solubility: 2.46e-03 mg/ml ; 6.26e-06 mol/l Class : Moderately soluble Log S (SILICOS-IT) : -5.50 Solubility: 1.23e-03 mg/ml ; 3.13e-06 mol/l Class : Moderately soluble |
GI absorption: High BBB permeant : No P-gp substrate : Yes CYP1A2 inhibitor : No CYP2C19 inhibitor : No CYP2C9 inhibitor : Yes CYP2D6 inhibitor : Yes CYP3A4 inhibitor : Yes Log Kp (skin permeation) : -6.31 cm/s |
Lipinski : Yes; 0 violation Ghose : Yes Veber : Yes Egan : Yes Muegge : Yes Bioavailability Score : 0.55 |
PAINS: 0 alert Brenk : 0 alert Leadlikeness: No; 1 violation: MW > 350 Synthetic accessibility : 3.18 |
| 4 |
Formula: C22H21N3O4 Molecular weight: 391.42 g/mol Num. heavy atoms: 29 Num. arom. heavy atoms: 18 Fraction Csp3: 0.23 Num. rotatable bonds: 3 Num. H-bond acceptors: 6 Num. H-bond donors: 2 Molar refractivity: 112.12 TPSA : 95.78 Å2 |
Log Po/w (iLOGP) : 2.41 Log Po/w (XLOGP3) : 2.23 Log Po/w (WLOGP) : 2.67 Log Po/w (MLOGP) : 0.91 Log Po/w (SILICOS-IT) : 3.34 Consensus Log Po/w : 2.31 |
Log S (ESOL) : -3.93 Solubility: 4.57e-02 mg/ml ; 1.17e-04 mol/l Class : Soluble Log S (Ali) : -3.88 Solubility: 5.20e-02 mg/ml ; 1.33e-04 mol/l Class : Soluble Log S (SILICOS-IT) : -6.10 Solubility: 3.14e-04 mg/ml ; 8.02e-07 mol/l Class : Poorly soluble |
GI absorption : High BBB permeant : No P-gp substrate : Yes CYP1A2 inhibitor : No CYP2C19 inhibitor : No CYP2C9 inhibitor : Yes CYP2D6 inhibitor : No CYP3A4 inhibitor : Yes Log Kp (skin permeation) : -7.10 cm/s |
Lipinski : Yes; 0 violation Ghose : Yes Veber : Yes Egan : Yes Muegge : Yes Bioavailability Score : 0.55 |
PAINS : 0 alert Brenk : 0 alert Leadlikeness : No; 1 violation: MW > 350 Synthetic accessibility : 3.35 |
| 5 |
Formula: C23H24N4O3 Molecular weight: 404.46 g/mol Num. heavy atoms: 30 Num. arom. heavy atoms: 18 Fraction Csp3: 0.26 Num. rotatable bonds: 6 Num. H-bond acceptors: 5 Num. H-bond donors: 2 Molar Refractivity: 121.13 TPSA : 89.79 Å2 |
Log Po/w (iLOGP) : 2.15 Log Po/w (XLOGP3) : 2.14 Log Po/w (WLOGP) : 2.00 Log Po/w (MLOGP) : 1.26 Log Po/w (SILICOS-IT) : 2.36 Consensus Log Po/w : 1.98 |
Log S (ESOL) : -3.74 Solubility: 7.29e-02 mg/ml ; 1.80e-04 mol/l Class : Soluble Log S (Ali) : -3.66 Solubility: 8.90e-02 mg/ml ; 2.20e-04 mol/l Class : Soluble Log S (SILICOS-IT) : -5.64 Solubility: 9.31e−04 mg/ml ; 2.30e−06 mol/l Class : Moderately soluble |
GI absorption : High BBB permeant : No P-gp substrate : Yes CYP1A2 inhibitor : No CYP2C19 inhibitor: No CYP2C9 inhibitor : No CYP2D6 inhibitor : Yes CYP3A4 inhibitor : Yes Log Kp (skin permeation) : -7.25 cm/s |
Lipinski : Yes; 0 violation Ghose : Yes Veber: Yes Egan : Yes Muegge : Yes Bioavailability Score : 0.55 |
PAINS : 0 alert Brenk : 0 alert Leadlikeness : No; 1 violation: MW > 350 Synthetic accessibility : 3.48 |
| 6 |
Formula: C23H24N2O4 Molecular weight: 392.45 g/mol Num. heavy atoms: 29 Num. arom. heavy atoms: 18 Fraction Csp3: 0.26 Num. rotatable bonds: 4 Num. H-bond acceptors: 6 Num. H-bond donors: 2 Molar Refractivity: 115.43 TPSA : 75.05 Å2 |
Log Po/w (iLOGP) : 3.57 Log Po/w (XLOGP3) : 3.21 Log Po/w (WLOGP) : 3.19 Log Po/w (MLOGP) : 1.59 Log Po/w (SILICOS-IT) : 3.90 Consensus Log Po/w : 3.09 |
Log S (ESOL) : -4.49 Solubility: 1.27e-02 mg/ml ; 3.23e-05 mol/l Class : Moderately soluble Log S (Ali) : -4.46 Solubility: 1.37e-02 mg/ml ; 3.48e-05 mol/l Class : Moderately soluble Log S (SILICOS-IT) : -6.66 Solubility: 8.51e-05 mg/ml ; 2.17e-07 mol/l Class : Poorly soluble |
GI absorption : High BBB permeant : Yes P-gp substrate : Yes CYP1A2 inhibitor : No CYP2C19 inhibitor : No CYP2C9 inhibitor : No CYP2D6 inhibitor : Yes CYP3A4 inhibitor : Yes Log Kp (skin permeation) : -6.41 cm/s |
Lipinski : Yes; 0 violation Ghose : Yes Veber : Yes Egan : Yes Muegge : Yes Bioavailability Score : 0.55 |
PAINS: 0 alert Brenk : 0 alert Leadlikeness : No; 1 violation: MW > 350 Synthetic accessibility : 3.42 |
| 7 |
Formula: C19H20ClN3O4 Molecular weight: 389.83 g/mol Num. heavy atoms: 27 Num. arom. heavy atoms: 12 Fraction Csp3: 0.37 Num. rotatable bonds: 3 Num. H-bond acceptors: 6 Num. H-bond donors: 3 Molar Refractivity: 107.67 TPSA : 94.92 Å2 |
Log Po/w (iLOGP) : 2.86 Log Po/w (XLOGP3) : 0.98 Log Po/w (WLOGP) : 0.64 Log Po/w (MLOGP) : 0.42 Log Po/w (SILICOS-IT) : 2.01 Consensus Log Po/w : 1.38 |
Log S (ESOL) : -3.01 Solubility: 3.85e-01 mg/ml ; 9.88e-04 mol/l Class : Soluble Log S (Ali) : -2.56 Solubility: 1.07e + 00 mg/ml ; 2.74e-03 mol/l Class : Soluble Log S (SILICOS-IT) : -4.49 Solubility: 1.25e-02 mg/ml ; 3.21e-05 mol/l Class : Moderately soluble |
GI absorption : High BBB permeant : No P-gp substrate : Yes CYP1A2 inhibitor : No CYP2C19 inhibitor : No CYP2C9 inhibitor : No CYP2D6 inhibitor : Yes CYP3A4 inhibitor : No Log Kp (skin permeation) : -7.98 cm/s |
Lipinski : Yes; 0 violation Ghose : Yes Veber : Yes Egan : Yes Muegge : Yes Bioavailability Score : 0.55 |
PAINS : 0 alert Brenk : 0 alert Leadlikeness : No; 1 violation: MW > 350 Synthetic accessibility : 3.77 |
| Staurosporine |
Formula: C28H26N4O3 Molecular weight: 466.53 g/mol Num. heavy atoms: 35 Num. arom. heavy atoms: 15 Fraction Csp3: 0.32 Num. rotatable bonds: 2 Num. H-bond acceptors: 4 Num. H-bond donors: 2 Molar Refractivity: 139.27 TPSA : 67.76 Å2 |
Log Po/w (iLOGP) : 3.26 Log Po/w (XLOGP3) : 1.97 Log Po/w (WLOGP) : 0.70 Log Po/w (MLOGP) : 1.87 Log Po/w (SILICOS-IT) : 2.01 Consensus Log Po/w : 1.96 |
Log S (ESOL) : -4.16 Solubility: 3.24e-02 mg/ml ; 6.94e-05 mol/l Class : Moderately soluble Log S (Ali) : -3.02 Solubility: 4.47e-01 mg/ml ; 9.58e-04 mol/l Class : Soluble Log S (SILICOS-IT) : -6.63 Solubility: 1.10e-04 mg/ml ; 2.37e-07 mol/l Class : Poorly soluble |
GI absorption : High BBB permeant : No P-gp substrate : Yes CYP1A2 inhibitor : Yes CYP2C19 inhibitor : Yes CYP2C9 inhibitor : No CYP2D6 inhibitor : Yes CYP3A4 inhibitor : Yes Log Kp (skin permeation) : -7.75 cm/s |
Lipinski : Yes; 0 violation Ghose : No; 1 violation: MR > 130 Veber : Yes Egan : Yes Muegge : No; 1 violation: #rings > 7 Bioavailability Score : 0.55 |
PAINS: 1 alert: ene_five_het_C Brenk : 0 alert Leadlikeness : No; 1 violation: MW > 350 Synthetic accessibility : 6.01 |