ADMET & DMPK 2(2) (2014) 107-114; doi: 10.5599/admet.2.2.

45

Open Access : ISSN : 1848-7718

http://www.pub.iapchem.org/ojs/index.php/admet/index
Original scientific paper

Evaluation of log Po/w values of drugs from some molecular

structure calculation software
Juan M. Pallicer1, Martí Rosés1, Clara Ràfols1, Elisabeth Bosch1*, Rosalia Pascual2,
Adriana Port2
1
Departament de Química Analítica and Institut de Biomedicina (IBUB), Universitat de Barcelona, Martí i Franquès 1-
11, 08028 Barcelona.
2
ESTEVE, Baldiri i Reixac, 4-8, 08028 Barcelona.

*Corresponding Author: Elisabeth Bosch, E-mail: e.bosch@ub.edu; Tel.: +34934021284; Fax: +34934021233
Received: July 04, 2014; Revised: July 11, 2014; Published: July 18, 2014

Abstract
Predictive software packages to estimate the lipophilicity of molecules have become key tools in the new
drug design. Six different well-known computational programs including the classical BioByte-clogP and
the GALAS algorithm offered by ACDlabs were evaluated through a set of 103 drugs with different
structures and functionalities. To evaluate the predictions accuracy, reliable experimental log Po/w values
for the whole testing set were carefully selected. The best estimations are performed by GALAS/logP based
on the fragmental method, corrected according to the similarity with compounds included in the software
training set.

Keywords: Lipophilicity of drugs, Lipophilicity prediction software

Introduction

Lipophilicity, expressed by the logarithm of octanol-water partition coefficient log P, or distribution log
D if ionised molecular species are present, constitutes a physicochemical property of paramount
importance in medicinal chemistry and in overall drug discovery. Optimal lipophilicity in compounds should
be targeted in the early phases of drug research since it contributes on individual ADMET (absorption,
distribution, metabolism, elimination and toxicology) [1,2], including blood-brain barrier penetration and
clearance [3].

Predictive software to estimate lipophilicity has also evolved as a master piece in the structure design
for new chemical entities [4]. Different methods for log P prediction have been developed and they can be
divided into two main categories, substructure-based and property-based methods.

Substructure-based methods work decomposing the 2D structure of the compound into fragments
(fragmental approaches) [5] or into single atoms (atom-based approaches) [6, 7]. The resulting log P value
is obtained as a summation of terms, being the difference among the different fragmental methods, the
set of fragments to identify in the target molecule, the contribution constant of each of those identified
fragments, and the different correction factors to apply depending on the fragment’s environment. In the

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Pallicer et al. ADMET & DMPK 2(2) (2014) 107-114

case of the atom-based methods there are commonly no correction factors in the summation and log P
values are obtained by adding the contribution of the different atom types present in the compound,
where different methods have different atom type definition and contribution values. In all cases the
different fragment references, atom type definitions and values are the result of different training sets and
analysis techniques used for the development of each method.

Property-based approaches [8] estimate log P values using calculated descriptors that account for the
entire molecule. Many of those techniques need the 3D structure of the compounds to calculate the
required descriptors, and variability of results due to conformational uncertainty has to be taken into
account. Some methods imply as well quantum mechanical semi-empirical calculations and others
molecular dynamics, which makes them resource demanding and slow. To overcome those difficulties
some linear models based on 2D-descriptors have been developed as well, however substructure-based
methods continue being the most widespread in the pharmaceutical world thanks to their speed and easy
implementation in MedChem Desktop tools and molecular modelling programs.

In this work, a set of 103 drugs which has been selected for representing a broad collection of
pharmaceutical compounds with different structures and functionalities, and a range of log Po/w values
from 0 to 7, has been used in order to evaluate the accuracy of the log Po/w values obtained through both
classical and well accepted programs such as the BioByte-ClogP and more recently developed ones as the
GALAS algorithm by ACD.

Calculation methods

A list of 103 pharmaceutical compounds with a wide variety of functionalities was selected to predict
log Po/w values through six different substructure-based methods: AlogP, which is an atom-based method
published by Ghose and Crippen [9] and implemented in PipelinePilot (Accelrys) [10], where carbon,
hydrogen, oxygen and nitrogen are classified into 120 atom types; clogP, a fragmental method with
correction factors that take structural and interaction factors into account, developed at the Pomona
College Medchem Project [11], licensed from BioByte Corp and incorporated in ChemFinder;
ChemProp/logP developed by Cambridge Soft and implemented in ChemFinder [12], it uses 3
fragmentation methods that can handle molecules containing different atoms; Classic ACD/logP [13],
which is based on contributions of separate atoms, structural fragments and intramolecular interactions
that have been derived form ACD/Labs internal database that comprises information from reference
books, articles and public sources; GALAS/logP [14], recently developed by ACD where its name stands for
Global, Adjusted Locally According to Similarity, the global method is as well fragmental and the baseline
result is adjusted depending on the performance obtained for similar compounds from the training set; and
Consensus/LogP [14] which is a consensus result on Classic and GALAS algorithms provided as well by ACD,
where dynamic adaptive coefficients are assigned to each model according to the corresponding
indications of prediction quality.

Results and Discussion

The log Po/w values obtained for the 103 compounds are gathered in Table 1. The reference log Po/w are
experimental values previously determined [15], complemented by the values recommended in BioLoom
online Database (Bioloom) and the “Gold standard” list selected by Avdeef [16]. In order to discover the

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ADMET & DMPK 2(2) (2014) 107-114 Evaluation of log P values

accuracy in used softwares, deviation obtained through experimental reference and predicted values are
listed. Colored values represent outliers where deviations are higher of 0.6 units. This limit value was
selected because of the experimental variability in log Po/w measurements that led the AOAC to admit
differences of 0.3 units between log Po/w values measured from replicates using the shaking flask reference
method as well as the variety of values shown for most compounds in the Leo et al [17] and Bioloom
databases [18].

Table 1. Predicted and experimental (reference) log P values.

Predicted log Po/w
ChemProp
log Po/w Classic Galas Consensus clogP AlogP
Name Deviation Deviation Deviation (Camdridge Deviation Deviation Deviation
Ref (ACD) (ACD) (ACD) (BioByte) (Accelrys)
Soft)
Vildagliptin -0.16 [15] -0.14 -0.02 1.39 -1.55 0.79 -0.95 -0.32 0.16 0.69 -0.85 0.18 -0.34
Theophylline -0.02 [18] -0.17 0.15 0.25 -0.27 0.13 -0.15 -1.03 1.01 -0.57 0.55 -0.31 0.29
Pilocarpine 0 [18] -0.10 0.10 0.62 -0.62 0.39 -0.39 0.54 -0.54 -0.20 0.20 0.97 -0.97
Atenolol 0.06 [15] 0.10 -0.04 0.29 -0.23 0.24 -0.18 0.50 -0.44 -0.11 0.17 0.67 -0.61
Amiloride 0.1 [18] 2.89 -2.79 -1.02 1.12 1.03 -0.93 -0.71 0.81 -2.22 2.32 -0.75 0.85
Levetiracetam 0.14 [18] -0.67 0.81 -0.76 0.90 -0.74 0.88 -0.75 0.89 -0.34 0.48 -0.30 0.44
Pyricarbate 0.24 [18] -0.25 0.49 0.51 -0.27 0.34 -0.10 0.67 -0.43 -0.42 0.66 0.65 -0.41
Sotalol 0.24 [18] 0.32 -0.08 0.28 -0.04 0.29 -0.05 -0.06 0.30 0.23 0.01 0.49 -0.25
Ranitidine 0.26 [15] 1.23 -0.97 0.22 0.04 0.37 -0.11 0.00 0.26 0.67 -0.41 1.04 -0.78
4-Aminophenazone 0.33 [18] 0.76 -0.43 1.18 -0.85 1.10 -0.77 0.36 -0.03 0.57 -0.24 0.99 -0.66
Pyridoxine 0.33 [18] -1.10 1.43 -0.39 0.72 -0.62 0.95 -0.49 0.82 -0.35 0.68 -0.49 0.82
Paracetamol 0.51[18] 0.34 0.17 0.43 0.08 0.40 0.11 0.89 -0.38 0.49 0.02 0.71 -0.20
Barbital 0.65 [18] 0.64 0.01 0.79 -0.14 0.76 -0.11 0.75 -0.10 0.66 -0.01 0.74 -0.09
Nadolol 0.71 [18] 1.29 -0.58 1.22 -0.51 1.24 -0.53 1.00 -0.29 0.38 0.33 1.15 -0.44
Sulfamethoxazole 0.89 [18] 0.89 0.00 0.58 0.31 0.65 0.24 0.86 0.03 0.56 0.33 0.71 0.18
Ephedrine 0.93 [18] 1.05 -0.12 1.33 -0.40 1.26 -0.33 1.38 -0.45 0.89 0.04 1.23 -0.30
Procainamide 1.09 [18] 1.10 -0.01 1.30 -0.21 1.25 -0.16 1.05 0.04 1.42 -0.33 1.13 -0.04
Codeine 1.14 [18] 1.20 -0.06 1.22 -0.08 1.21 -0.07 1.45 -0.31 0.98 0.16 1.64 -0.50
Triamterene 1.22 [18] 1.34 -0.12 1.16 0.06 1.20 0.02 2.11 -0.89 1.61 -0.39 1.02 0.20
Cortisone 1.47 [18] 1.44 0.03 1.46 0.01 1.46 0.01 0.82 0.65 1.30 0.17 1.24 0.23
Phenobarbital 1.47 [18] 1.67 -0.20 1.30 0.17 1.41 0.06 1.52 -0.05 1.37 0.11 1.32 0.15
Morin 1.56 [18] 1.61 -0.05 1.78 -0.22 1.74 -0.18 0.35 1.21 1.13 0.43 1.63 -0.07
Clonidine 1.57 [16] 1.41 0.16 2.05 -0.48 1.80 -0.23 2.78 -1.21 1.73 -0.16 2.35 -0.78
Hydrocortisone 1.61 [18] 1.43 0.18 1.72 -0.11 1.66 -0.05 0.50 1.11 1.70 -0.09 1.28 0.33
Sulfadimethoxine 1.63 [18] 1.48 0.15 1.45 0.18 1.46 0.17 1.39 0.24 1.98 -0.35 1.36 0.27
Ketorolac 1.68 [18] 2.08 -0.40 2.71 -1.03 2.58 -0.90 1.64 0.04 1.62 0.06 2.83 -1.15
Sulfaquinoxaline 1.68 [18] 1.30 0.38 1.64 0.04 1.56 0.12 1.52 0.16 1.69 -0.01 1.57 0.11
Bromazepam 1.69 [18] 1.65 0.04 2.18 -0.49 2.09 -0.40 2.10 -0.41 1.70 -0.01 2.33 -0.64
Acebutolol 1.71 [18] 1.95 -0.24 1.58 0.13 1.68 0.03 0.94 0.77 1.71 0.00 1.62 0.10
Benzthiazide 1.73 [18] 2.63 -0.90 1.75 -0.02 2.04 -0.31 2.30 -0.57 2.11 -0.38 1.97 -0.24
Omeprazole 1.8 [16] 2.17 -0.37 2.07 -0.27 2.09 -0.29 2.17 -0.37 2.02 -0.22 2.90 -1.10
Atropine 1.83 [18] 1.53 0.30 1.95 -0.12 1.86 -0.03 1.53 0.30 1.30 0.53 1.72 0.11
Metoprolol 1.88 [18] 1.79 0.09 1.88 0.00 1.85 0.03 1.72 0.16 1.49 0.39 1.76 0.12
Corticosterone 1.94 [18] 1.76 0.18 2.20 -0.26 2.10 -0.16 1.26 0.68 2.32 -0.38 2.02 -0.08
Bendroflumethiazide 1.95 [18] 2.07 -0.12 1.32 0.63 1.49 0.46 2.22 -0.27 1.73 0.22 1.86 0.09
Mepivacaine 1.95 [18] 2.04 -0.09 1.86 0.09 1.91 0.04 2.62 -0.67 2.10 -0.15 2.98 -1.03
Milnacipran 2.03 [18] 1.23 0.80 1.94 0.09 1.66 0.37 1.63 0.40 1.91 0.12 1.29 0.74
Flunitrazepam 2.06 [18] 1.44 0.62 2.07 -0.01 2.03 0.03 1.42 0.64 1.78 0.28 2.61 -0.55
Oxprenolol 2.1 [18] 2.29 -0.19 2.29 -0.19 2.29 -0.19 2.22 -0.12 2.09 0.01 2.23 -0.13
Pentobarbital 2.1 [18] 2.05 0.05 2.01 0.09 2.02 0.08 1.91 0.19 2.11 -0.01 1.91 0.19
Clobazam 2.12 [18] 1.69 0.43 2.44 -0.32 2.29 -0.17 2.57 -0.45 2.44 -0.32 2.74 -0.62
Carbamazepine 2.19 [18] 2.67 -0.48 2.17 0.02 2.28 -0.09 2.93 -0.74 2.38 -0.19 2.68 -0.49
Spironolactone 2.26 [18] 3.12 -0.86 2.68 -0.42 2.78 -0.52 2.90 -0.64 2.65 -0.39 3.73 -1.47
Clonazepam 2.41 [18] 2.34 0.07 2.57 -0.16 2.53 -0.12 2.18 0.23 2.38 0.03 2.86 -0.45
Chlordiazepoxide 2.44 [18] 2.16 0.28 2.39 0.05 2.36 0.08 1.72 0.72 3.79 -1.35 2.30 0.14
Naringenin 2.52 [18] 3.19 -0.67 2.49 0.03 2.62 -0.10 1.63 0.89 2.44 0.08 2.37 0.15
Rosuvastatin 2.52 [15] 0.42 2.10 1.90 0.62 1.36 1.16 0.59 1.93 1.90 0.62 2.43 0.09
Clofibric acid 2.57 [18] 2.72 -0.15 2.74 -0.17 2.74 -0.17 2.62 -0.05 2.82 -0.25 2.76 -0.19
Furosemide 2.6 [18] 3.10 -0.50 2.21 0.39 2.35 0.25 0.74 1.86 1.90 0.70 1.40 1.20
Hesperetin 2.6 [18] 2.90 -0.30 2.57 0.03 2.66 -0.06 1.50 1.10 2.29 0.31 2.36 0.24
Cinchonidine 2.62 [18] 3.35 -0.73 2.79 -0.17 2.92 -0.30 2.60 0.02 2.49 0.13 2.75 -0.13
Quinine 2.64 [18] 3.46 -0.82 2.86 -0.22 3.02 -0.38 2.60 0.04 2.99 -0.35 2.99 -0.35
Lidocaine 2.65 [18] 2.36 0.29 2.32 0.33 2.33 0.32 2.41 0.24 1.95 0.70 2.63 0.02
Tramadol 2.7 [15] 2.51 0.19 2.55 0.15 2.54 0.16 2.53 0.17 3.10 -0.40 2.70 0.00
Lormetazepam 2.72 [16] 2.31 0.41 2.61 0.11 2.57 0.15 3.88 -1.16 2.40 0.32 3.71 -0.99
Xipamide 2.8 [18] 2.50 0.30 2.99 -0.19 2.88 -0.08 2.73 0.07 1.93 0.87 2.71 0.09
Trazodone 2.82 [18] 1.66 1.16 3.21 -0.39 2.77 0.05 2.94 -0.12 3.85 -1.03 2.42 0.40
Diltiazem 2.84 [15] 3.63 -0.79 3.38 -0.54 3.43 -0.59 2.64 0.20 3.65 -0.81 3.09 -0.25
Brompheniramine 2.88 [18] 3.57 -0.69 3.23 -0.35 3.33 -0.45 3.89 -1.01 3.30 -0.42 3.78 -0.90
Alprenolol 2.89 [18] 2.88 0.01 2.74 0.15 2.78 0.11 2.70 0.19 2.65 0.24 2.64 0.25
Propranolol 2.98 [18] 3.10 -0.12 3.32 -0.34 3.26 -0.28 2.65 0.33 2.75 0.23 2.54 0.44
Diazepam 2.99 [18] 2.91 0.08 2.92 0.07 2.92 0.07 2.98 0.01 2.96 0.03 3.17 -0.18

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Apigenin 3.02 [18] 2.10 0.92 2.59 0.43 2.45 0.57 1.90 1.12 2.91 0.11 2.41 0.61
Venlafaxine 3.05 [15] 2.91 0.14 3.33 -0.28 3.15 -0.10 2.81 0.24 3.27 -0.22 3.02 0.03
Rosiglitazone 3.1 [15] 2.56 0.54 2.87 0.23 2.75 0.35 3.21 -0.11 3.02 0.08 3.27 -0.17
Pyrilamine 3.12 [18] 2.75 0.37 3.14 -0.02 3.05 0.07 3.30 -0.18 3.23 -0.11 3.09 0.03
Quetiapine 3.13 [15] 1.57 1.56 2.95 0.18 2.37 0.76 3.91 -0.78 2.99 0.14 2.66 0.47
Ketoprofen 3.14 [18] 2.81 0.33 3.27 -0.13 3.12 0.02 3.31 -0.17 2.76 0.38 3.36 -0.22
Chlorphenamine 3.17 [18] 3.39 -0.22 2.95 0.22 3.09 0.08 3.62 -0.45 3.15 0.02 3.70 -0.53
Fenbufen 3.2 [18] 3.13 0.07 3.22 -0.02 3.21 -0.01 2.34 0.86 3.14 0.06 2.93 0.27
Naproxen 3.24 [15] 3.00 0.24 2.98 0.26 2.98 0.26 2.86 0.38 2.82 0.42 2.85 0.39
Warfarin 3.25 [18] 3.42 -0.17 2.99 0.26 3.11 0.15 2.97 0.28 2.90 0.35 2.83 0.42
Diphenhydramine 3.27 [18] 3.66 -0.39 3.72 -0.45 3.71 -0.44 3.25 0.02 3.45 -0.18 3.38 -0.11
Bupivacaine 3.41 [18] 3.64 -0.23 2.87 0.54 3.08 0.33 3.86 -0.45 3.69 -0.28 4.31 -0.90
Clotiazepam 3.49 [18] 3.05 0.44 3.01 0.48 3.02 0.47 3.91 -0.42 3.03 0.46 3.77 -0.28
Chrysin 3.52 [18] 2.88 0.64 3.24 0.28 3.11 0.41 2.29 1.23 3.56 -0.04 2.65 0.87
Valsartan 3.59 [18] 4.75 -1.16 3.52 0.07 3.87 -0.28 0.00 3.59 3.63 -0.04 4.54 -0.95
Haloperidol 3.82 [18] 3.01 0.81 3.61 0.21 3.48 0.34 3.49 0.33 3.85 -0.03 3.89 -0.07
Flurbiprofen 3.84 [15] 4.12 -0.28 3.71 0.13 3.82 0.02 3.18 0.66 3.75 0.09 3.68 0.16
Progesterone 3.87 [18] 4.04 -0.17 3.58 0.29 3.72 0.15 3.78 0.09 3.78 0.10 3.86 0.01
Celecoxib 3.91 [18] 4.21 -0.30 3.02 0.89 3.24 0.67 4.34 -0.43 4.37 -0.46 4.43 -0.52
Flurazepam 3.94 [18] 3.99 -0.05 3.47 0.47 3.55 0.39 3.81 0.13 4.22 -0.28 4.21 -0.27
Glimepiride 3.97 [15] 2.94 1.03 3.44 0.53 3.17 0.80 2.59 1.38 3.96 0.01 3.78 0.19
Ibuprofen 3.97 [18] 3.72 0.25 3.21 0.76 3.37 0.60 3.14 0.83 3.68 0.29 3.61 0.36
Atorvastatin 4.08 [15] 4.13 -0.05 4.43 -0.35 4.36 -0.28 5.05 -0.97 4.46 -0.38 5.56 -1.48
Indometacin 4.1 [15] 3.10 1.00 4.48 -0.38 4.02 0.08 3.69 0.41 4.18 -0.08 4.24 -0.14
Nortriptyline 4.36 [18] 5.65 -1.29 4.41 -0.05 4.76 -0.40 4.25 0.11 4.32 0.04 4.24 0.12
Loratadine 4.4 [18] 5.94 -1.54 5.15 -0.75 5.32 -0.92 4.13 0.27 5.05 -0.65 5.00 -0.60
Fluoxetine 4.42 [15] 4.09 0.33 4.35 0.07 4.27 0.15 4.27 0.15 4.57 -0.15 4.03 0.39
Diclofenac 4.5 [18] 4.06 0.44 4.61 -0.11 4.48 0.02 4.12 0.38 4.73 -0.23 4.37 0.13
Clopidogrel 4.52 [15] 4.23 0.29 4.20 0.32 4.21 0.31 3.74 0.78 4.21 0.31 3.74 0.79
Duloxetine 4.54 [15] 3.73 0.81 4.17 0.37 4.03 0.51 4.33 0.21 4.26 0.28 3.85 0.69
Penbutolol 4.62 [16] 4.17 0.45 3.84 0.78 3.97 0.65 3.44 1.18 3.64 0.98 3.57 1.05
Maprotiline 4.67 [18] 4.51 0.16 5.23 -0.56 4.95 -0.28 4.59 0.08 4.52 0.15 4.12 0.55
Imipramine 4.8 [18] 4.80 0.00 4.65 0.15 4.69 0.11 4.32 0.48 5.04 -0.24 4.39 0.41
Amitriptyline 4.92 [18] 4.92 0.00 4.67 0.25 4.72 0.20 4.42 0.50 4.85 0.07 4.77 0.15
Cyproheptadine 4.92 [18] 6.41 -1.49 4.65 0.27 5.05 -0.13 3.97 0.95 5.30 -0.38 4.36 0.56
Sertraline 5.17 [15] 4.81 0.36 5.40 -0.23 5.18 -0.01 5.03 0.14 5.35 -0.18 5.00 0.17
Flufenamic acid 5.19 [15] 5.62 -0.43 5.26 -0.07 5.34 -0.15 3.98 1.21 5.53 -0.34 3.95 1.24
Chlorpromazine 5.27 [15] 5.20 0.07 5.42 -0.15 5.36 -0.09 4.24 1.03 5.30 -0.03 4.74 0.53
Miconazole 5.34 [18] 5.93 -0.59 6.28 -0.94 6.20 -0.86 5.09 0.25 5.81 -0.47 5.65 -0.31
Rimonabant 5.57 [18] 6.01 -0.44 5.27 0.30 5.45 0.12 6.28 -0.71 6.47 -0.90 6.61 -1.04
Clofazimine 6.3 [18] 7.26 -0.96 7.49 -1.19 7.44 -1.14 5.39 0.91 7.70 -1.40 7.14 -0.84
Mean = -0.01 -0.02 -0.01 0.22 0.00 -0.07
SD = 0.65 0.43 0.41 0.71 0.47 0.55

According to the differences of Table 1, clogP, Classic ACD/logP, Consensus/logP, and Galas/logP are the
most accurate methods with mean deviations very close to 0. The precision of clogP, Consensus/logP, and
Galas/log P is also very good with a standard deviation between 0.4 and 0.5 logP unities. The standard
deviation of Classic/logP is somewhat larger (0.65). AlogP is less accurate and precise (mean of -0.07 and
standard deviation of 0.55) and ChemProp has the poorest accuracy and precision (mean of deviations of
0.22 and standard deviation of 0.71).

Figure 1 shows the correlation between the results of the calculation by the 6 different methods and
reference log Po/w values and Table 2 the regression coefficients (R2) and standard deviations obtained for
those correlations. All methods give good linear correlations with R2 values between 0.79 and 0.93.The
results presented in Table 2 are consistent with those of Table 1. Consensus/logP and Galas/logP give the
best results: they give exact results because the slopes and intercepts are not different from 1 and 0,
respectively, at 95 % confidence level, but also the most precise (with the lowest overall standard
deviations, 0.43 and 0.41). AlogP, Classic ACD/logP and ChemProp/logP have also slopes and intercepts not
significantly different from 1 and 0, giving thus exact results but less precise (SD of 0.55, 0.66 and 0.70,
respectively). The number of outliers for these last methods is higher too (Table 3). clogP gives quite
precise results (SD = 0.46) but it shows a slope slightly higher than one and an intercept lower than zero.
Thus, clogP may predict slightly negative deviations for hydrophilic compounds but positive deviations for
hydrophobic ones. In fact, all methods have a lower prediction power for extreme ranges of log Po/w values,

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ADMET & DMPK 2(2) (2014) 107-114 Evaluation of log P values

being the range of compounds with log P higher than 5 where accuracy tends to be poorer. This can be
seen in Table 3 which reports the number of outliers in the respective log P ranges.

Figure 1. Comparative linear relationship between log P reference and the different predictive log P
softwares (n =103).

Table 2. Regression coefficients and standard deviations for the different predictive log P softwares.

Classic Galas Consensus ChemProp clogP AlogP

2
R 0.84 0.92 0.93 0.79 0.93 0.87
SD 0.66 0.43 0.41 0.70 0.46 0.55
Y=a+bX a (SD) 0.00 (±0.13) 0.09 (±0.09) 0.09 (±0.08) 0.02 (±0.14) -0.23 (±0.09) 0.23 (±0.11)
b (SD) 1.00 (±0.04) 0.97 (±0.03) 0.97 (±0.03) 0.91 (±0.05) 1.09 (±0.03) 0.94 (±0.04)

Table 3. Number of outliers with deviations higher than 0.6 units for the different predictive log P softwares and the
different ranges of log Po/w reference values.
*
n Classic Galas Consensus ChemProp clogP AlogP
log Pref>5 6 1 2 2 4 2 3
5<log Pref>1 81 22 7 8 30 9 19
log Pref<1 16 4 6 5 4 4 6
*
n is the total number of compounds in the log P range

Although Galas/logP and Consensus/logP values seem to be the most accurate methods for this set of
compounds it has to be taken into account that the result of the fragmental method in those programs is
just a baseline value, which is corrected adding a similarity weighted average from the differences between
the baseline predictions and the experimental data for the most similar compounds in the training set to
the submitted compound. This strategy must achieve to best fit the training set data, but the quality of the
results for other compounds will depend a lot on the similarity of those to the training set. This may be

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quite high in our case, being all the 103 compounds known pharmaceutical compounds with public
experimental values. In fact we have observed that at least for 87 compounds out of the 103, the same
compound could be found in the training set, being their initial prediction therefore corrected to the
experimental value with the highest weight. This handicap is overcome in clogP where results obey
exclusively to the general formula, fragments, correction factors and coefficients developed for the
method. In fact this method shows almost the same predictability than Galas/logP, the least number of
outliers or unacceptable predictions (>0.6) among all methods, and it has better results than Classic
ACD/logP and AlogP for this set of compounds. Finally, ChemProp shows the poorest performance
according to accuracy, precision, and number of outliers.

In order to observe the performance of Galas/logP and Consensus/logP for compounds that are not part
of the training set, we have evaluated the prediction for the remaining 16 compounds, being the results
shown in Figure 2. We show the comparison as well for the remaining methods although in those cases we
do not know whether those 16 compounds are part of the training set or not. We can see in Table 4 that
accuracy of predictions for Galas/logP has diminished while clogP, Classic ACD/logP and AlogP predictions
retain their predictability levels.

Figure 2. Comparative linear relationship between log P reference and the different predictive log P
softwares (n =16: compounds not in ACD training set).

Table 4. Regression coefficients and standard deviations for the different predictive logP softwares (n =16: compounds
not in ACD training set).

Classic Galas Consensus ChemProp clogP AlogP

2
R 0.78 0.83 0.84 0.58 0.93 0.80
SD 0.82 0.48 0.54 1.25 0.42 0.69
Y=a+bX a (SD) -0.37 (±0.52) 0.96 (±0.31) 0.48 (±0.34) -0.20 (±0.79) 0.20 (±0.27) 0.51 (±0.44)
b (SD) 1.02 (±0.15) 0.72 (±0.09) 0.82 (±0.10) 0.98 (±0.22) 0.98 (±0.07) 0.92 (±0.12)

In any case to better estimate the performance of the methods, it would be desirable to compare
calculated versus experimental log Po/w value for a larger set of highly diverse compounds that had low
structural similarity to compounds in the training set. It is worth to mention that to leverage that,

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ADMET & DMPK 2(2) (2014) 107-114 Evaluation of log P values

Galas/logP offers the possibility to enlarge the training set with new compounds and their determined
experimental data, which might be of use when predicting lipophilicity for analogs of on-going chemistry
within a discovery program.

At that point we would like to stress that all the predictive software are initiated from experimental
values obtained from the literature and not in all cases literature values of different sources coincide. To
study those differences in some depth we used the mentioned 87 compounds that are at the same time
part of ACD’s training set and compared our reference experimental log Po/w values as summarize in Table 1
with the ACD reference experimental log Po/w values. We have centered our comparison on those ACD
values as the experimental log Po/w values used to train the ACD models can be directly obtained within the
software, however other training sets used to derive clogP or AlogP are not so easily available.

We observe that the values do not show a perfect correlation (Figure 3). A slope of 0.92 and a
y-intercept of 0.2 are obtained. Although the variability in the experimental determination is a fact fully
known, it is important to have that correlation value between experimental measures in mind when
evaluating prediction methods, as in light of this, we cannot expect to obtain a correlation between
experimental and predicted values higher than the 0.95.

7
y = 0.9169x + 0.2185
6 R2 = 0.9452
Used LogP o/w ref

-1
-1 0 1 2 3 4 5 6 7 8

ACD LogP o/w ref

Figure 3. Linear relationship between log Po/w used in ACD database and the log P o/w reference used in
this study (n=87).

Conclusions

All tested substructure-based methods have an acceptable accuracy and precision for estimating the
lipophilicity of pharmaceutical compounds, where predictions tend to loose accuracy in the extreme
ranges.

In the case of our dataset Consensus/logP and Galas/logP show the best results, however being the
globally predicted values corrected depending on the performance of the method for the most similar
compounds, and being our 103 compounds known pharmaceutical compounds, an analysis for a set of
highly diverse compounds that had low structural similarity to compounds in the training set would be
needed to verify its precision in evaluating log P values of a general dataset of compounds. Among the
other methods that do not apply any structural analog approach clogP is performing best whereas
ChemProp/logP is showing the lowest predictability.

doi: 10.5599/admet.2.2.45 113

Pallicer et al. ADMET & DMPK 2(2) (2014) 107-114

Acknowledgements: Financial support from the Ministerio de Ciencia e Innovación of the Spanish
Government and the Fondo Europeo de Desarrollo Regional (FEDER) of the European Union (Project
CTQ2010-19217/BQU) is acknowledged.

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