Table III.
Information Around the in-House QSAR Models and Descriptors used to Build the Log%SDiP OPLS Model
| QSAR model / Descriptor | Details | Coefficients with regards to IPRLu QSAR model |
|---|---|---|
| FA_rat_v1.logFA_score | Output from an inhouse QSAR model that predicts fraction absorbed in the rat, this model was built on a GSK rat oral bioavailability dataset with total clearance values of less than 10 ml/min/kg and therefore minimal first pass effect. | + |
| Perm_chrom_p.perm_score | An inhouse PLS-Discriminant analysis model which predicts permeability and oral absorption of compounds. | + |
| MDCK2.Perm_pH74_nm_sec MDCK2.Perm_pH64_nm_sec | Inhouse QSAR models which predict passive permeability across a madine darby canine kidney (MDCK) cell monolayer (31) with donor solutions buffered at pH7.4 and pH6.4. | + |
| Pgp_v31.Pgp_Score | An inhouse PLS-Discriminant analysis model which predicts the likelihood of a compound being a substrate for the ABC active efflux transporter P-glycoprotein. | + |
| Chrom LogD_v3.value | An inhouse OPLS QSAR model that predicts hydrophobicity, the model was built on a GSK dataset of chromatographic hydrophobicity index (CHI) measurements (32) which are converted to a chromLogD value (4). | + |
| neutral_ionised_form | % of the molecule in the neutral form at pH7.4. pKa’s calculated using the ACDlabs softwarea ACD_v11. | + |
| logd_pH55_acd | Calculated logD value from the ACDlabs software at pH5.5 | + |
| logd_pH65_acd | Calculated logD value from the ACDlabs software at pH6.5 | + |
| Bpka1_modified | The most basic pka value calculated using ACDlabs software ACD_v11 | – |
| basic_ionised_form | % of the molecule in the acidic form at pH7.4 pKa’s calculated using the ACDlabs software ACD_v11. | – |
| abe | Andrews Binding energy (33). | – |
| cmr | Calculated molar refraction | – |
| mw | Average molecular weight of parent | – |
| tpsa | Polar surface area calculated by the method of Ertl (34). | – |
| hbd | Count of the number of hydrogen bond acceptors in a molecule. | – |
| pos | The count of the number of positively ionisable/charged groups in a molecule. | – |
| rb | count of the number of rotatable bonds in a molecule. | – |
| flex | related to the ratio of the number of rotatable bonds to total bonds = int(100*rotatable_bonds/total_bonds) | - |
| alpha | An Abraham’s molecular descriptor relating to Hydrogen Bond Acidity (hydrogen bond donors) (30). | - |
| betah | An Abraham’s molecular descriptor relating to Hydrogen Bond Basicity (hydrogen bond acceptors) (30). | - |
| pi | An Abraham’s molecular descriptor relating to the dipolarity/dipolarizability (30). | - |
| vx | An Abraham’s molecular descriptor relating to McGowan characteristic volume (size) (30). | - |
| total_HB | Sum of hydrogen bond donors and acceptors (physchem_desc.hba + physchem_desc.hbd) | - |
| total_charge | Sum of positive and negative charges (physchem_desc.neg + physchem_desc.pos) | - |
| nonPSA | Approximation of total surface area - polar surface area. | - |
aACDlabs software: Advanced Chemistry Development, Inc. 8 King Street East, Suite 107, Toronto, Ontario, Canada M5C 1B5