ADME Model Information

• Lipinski Violations: (1) MW > 500,  (2) Num_H_Accs > 10,  (3) Num_H_Donors > 5, (4) AlogP > 6; (ref: Lipinski et al, Advanced Drug Delivery Reviews 46, 2001, 3–26)
• REOS Features: Structures deemed inappropriate for HTS; (ref: Rishton, Drug Discovery Today, 2, 9, Sept 1997; M. Hann et al.  J. Chem. Inf. Comput. Sci. 39, 1999, 897–902.; Walters et al, Advanced Drug Delivery Reviews 54, 2002, 255–271; consultations with Medicinal Chemists)
• Intestinal Permeability Model (%Abs): (a) 0 = Very Low Absorption; (b) 1 = Low Absorption; (c) 2 = Moderately absorbed; (d) 3 = Well absorbed (>90%); (ref: Egan et al, J. Med. Chem. 2000,43, 3867–3877; Egan, W.J., Lauri, G., Adv. Drug Del. Rev., 54, 273, 2001)
• ADMET Solubility Model (Log mol/L): (a) 0 = Extremely Low Solubility (<-8.0); (b) 1 = Very Low Solubility (-8.0 – -6.0); (c) 2 = Low Solubility (-6.0 – -4.0); (d) 3 = Moderate Solubility (-4.0 – -2.0); (e) 4 = Optimal Solubility (-2.0 – 0.0); (f) 5 = Very Soluble (>0.0); (g) 6 = Undefined; (ref: Cheng, A. and Merz, Jr., K. "Prediction of aqueous solubility of a diverse set of compounds using quantitative structure-property relationships," J. Med. Chem. 2003, 46, 3572–3580).
• TETKO Solubility Model (Log mol/L): (a) 0 = Extremely Low Solubility (<-8.0); (b) 1 = Very Low Solubility (-8.0 – -6.0); (c) 2 = Low Solubility (-6.0 – -4.0); (d) 3 = Moderate Solubility (-4.0 – -2.0), (e) 4 = Optimal Solubility (-2.0 – 0.0); (f) 5 = Very Soluble (>0.0); (ref: Scitegic's Pipeline Pilot model based on Tetko et al.,J Chem Inf. Comput. Sci, 2001, 41, 1488–1493, "Estimation of Aqueous Solubility of Chemical Compounds Using E-State Indices)
• Blood Brain Barrier (BBB) Permation: (a) 0 = Undefined; (b) 1 = Outside Confidence Range; (c) 2 = Low Permation (Blood:Brain > 0.3); (d) 3 = Medium Permation (Blood:Brain 0.3 > 1:1); (e) 4 = High Permeation Brain:Blood 1:1 > 5:1); (f) 5 = Very High Permation (Blood:Brain > 5:1); (ref: Accelrys Proprietary model);
• Plasma Protein Binding (PPB): (a) 0 = <90%; (b) 1 = >=90%, (c) 2 = >95%; (ref: Dixon, S.L. and Merz, K.M.M., Jr. "One-Dimensional Molecular Representations and Similarity Calculations: Methodology and Validation," J. Med. Chem., 2001, 44, 3795–3809.)
• CYP 2D6 Inhibition: (a) 0 = Non-Inhibitor; (b) 1 = Inhibitor; (ref: Dixon, S.L., Villar, H.O., J. Comput. Aided Mol. Design, 13, 533 (1999).; Susnow, R.G., Dixon, SL, "Use of robust classification techniques for the prediction of human cytochrome P450 2D6 inhibition," J. Chem. Inf. Comput. Sci., 2003, 43, 1308–1315)
• Hepatotoxicity: (a) 0 = Not Toxic; (b) 1 = Toxic; (ref: Dixon, SL; Villar, H.O., J. Comput. Aided Mol. Design, 13, 533 (1999); Cheng, A. and Dixon, SL In silico models for the prediction of dose-dependent human hepatotoxicity, J. Comput. Aided Mol. Design, 17, 811–823. (2003));
• Ghose Violations: (1) -0.4 <= AlogP <= 5.6, (2) 160 <= MW <= 480, (3) 40 <= MR <= 130, (4) 20 <= Num_Atoms <= 70; (ref: A.K. Ghose et al, J. Comb. Chem. 1, 1999, 55–67)
• Oprea Violations: (1) Num_H_Donors > 2, (2) 2 <= Num_H_Accs <= 9, (3) 2 <= Num_RBs <= 8, (4) 1 <= Num_Rings <= 4; (ref: Oprea, Journal of Computer-Aided Molecular Design, 14: 251–264, 2000)
• Suspect Substructure Violations: Compounds gleamed from medicinal chemistry literature that are known to be problematic for developing drug candidates