Review

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Lipophilicity in drug design: an overview of

lipophilicity descriptors in 3D-QSAR studies
Tiziana Ginex*,1 , Javier Vazquez1,2 , Enric Gilbert2 , Enric Herrero2 & Francisco J Luque**,1
1
Department of Nutrition, Food Sciences & Gastronomy, Faculty of Pharmacy & Food Sciences, Campus Torribera, Institute of
Biomedicine (IBUB), & Institute of Theoretical & Computational Chemistry (IQTC-UB), University of Barcelona, Av. Prat de la Riba
171, Santa Coloma de Gramenet E-08921, Spain
2
Pharmacelera, Plaça Pau Vila, 1, Sector 1, Edificio Palau de Mar, Barcelona 08039, Spain
*Author for correspondence: [email protected]
**Author for correspondence: [email protected]

The pharmacophore concept is a fundamental cornerstone in drug discovery, playing a critical role in de-
termining the success of in silico techniques, such as virtual screening and 3D-QSAR studies. The reliability
of these approaches is influenced by the quality of the physicochemical descriptors used to characterize the
chemical entities. In this context, a pivotal role is exerted by lipophilicity, which is a major contribution to
host–guest interaction and ligand binding affinity. Several approaches have been undertaken to account
for the descriptive and predictive capabilities of lipophilicity in 3D-QSAR modeling. Recent efforts encode
the use of quantum mechanical-based descriptors derived from continuum solvation models, which open
novel avenues for gaining insight into structure–activity relationships studies.

First draft submitted: 30 August 2018; Accepted for publication: 4 February 2019; Published online:
25 February 2019

Keywords: 3D-QSAR • continuum solvation models • hydrophobic pharmacophore • lipophilicity • quantum

mechanical-derived descriptors

The pharmacophore concept & its application in drug design

Almost all processes of life are determined by the recognition between biomolecules, a process dictated by the
chemical complementarity between the interacting partners [1]. An effective characterization of the chemical features
associated with the structure of both ‘host’ and ‘guest’ is necessary for disclosing the key molecular determinants
implicated in the formation of the host–guest complex. In drug discovery studies addressing the interaction of small
molecules (ligands) with macromolecular receptors, these determinants are generally encoded under the concept
of pharmacophore. A simple and intuitive definition can be attributed to Paul Ehrlich, since this concept can be
related to “a molecular framework that carries (phoros) the essential features responsible for a drug’s (pharmacon) biological
activity” [2]. Nevertheless, Ehrlich did not use the term pharmacophore in his papers, where the terms haptophore
and toxophore were adopted [3]. Instead, the modern concept of pharmacophore evolved from the identification
of ‘chemical groups’ to the definition as “patterns of abstract features in space” by Schueler [4], reflected in early
models depicting key features for biological activity that must satisfy certain geometrical relationships [5,6], and the
development of the first pharmacophore pattern recognition programs [7]. Thus, according to the International
Union of Pure and Applied Chemistry (IUPAC), a pharmacophore “does not represent a real molecule or a real
association of functional groups, but a purely abstract concept that accounts for the common molecular interaction
capacities of a group of compounds toward their target structure,” being the largest common denominator shared by a
set of active molecules [8].
This evolution has been accompanied by the progressive refinements triggered by advances in molecular de-
scriptors and computational methods seen in the last 30 years, since a variety of in silico techniques have exploited
the pharmacophore concept. This is exemplified by virtual screening (VS) studies of large molecular databases
performed to identify new promising compounds according to their similarity to a given privileged template,
which should contain reference physicochemical features relevant for biological activity [9–11]. Molecular/chemical
(global/local) similarity is a subjective concept since it depends on the specific details of the methodological ap-

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Review Ginex, Vazquez, Gilbert, Herrero & Luque

proach, the nature of the molecular features relevant for similarity assessment, and the definition of the similarity
function [12]. A sensitive and effective estimation of molecular similarity is a fundamental pre-requisite for the
identification of potential leads starting from a chemical reference, which represents the paradigm of VS.
Another successful application of the pharmacophore concept is linked to 3D-quantitative structure–activity
relationships (3D-QSAR) [13], such as CoMFA [14], CoMSIA [15] and GRID/GOLPE [16]. These methods permit
to identify a pharmacophore from the relationships between the biological activities of a set of aligned molecules
and the projection of selected physicochemical descriptors into the surrounding space, leading to the disclosure of
regions favorable or not to the bioactivity of compounds. 3D-QSAR approaches are also used to model ADME(T)
properties in the attempt to predict whether a molecular candidate would be able to achieve its biological target [17].
Optimization of both ligand potency and ADME(T) profile is absolutely required to translate promising molecular
candidates to successful low-dose therapeutics. However, the success of this operation is not trivial, since the final
result depends on factors such as the quality of the input data, as well as the adequacy and level of description of the
physicochemical parameters used in the analysis. In fact, Gleeson and collaborators [18] have observed the existence
of a diametrically opposed relationship between descriptors that efficaciously model drug potency and ADME(T)
properties, making more challenging the drug discovery process.

Lipophilicity in drug design

The relevance of lipophilicity in understanding the pharmacological profile of drug-like compounds is widely
recognized [19], as a broad variety of biodistribution and toxicological processes are ultimately related to the
differential solubility of solutes in aqueous and nonaqueous environments. This is illustrated by Lipinski’s rule-
of-five [20], which relates the drug-likeness of oral compounds with molecular weight, hydrogen bonding and
lipophilicity. Being a key property for the prediction of ADME(T) properties, this has stimulated the development
of experimental and computational approaches to quantify the lipophilicity of a (bio)organic molecule.
Experimentally, the lipophilicity of a molecule can be quantified by its partition coefficient (P), as this equilibrium
thermodynamic property measures the ratio of concentrations of the compound between two immiscible solvents,
generally water and n-octanol. In turn, the partition coefficient can be expressed in terms of the transfer free energy
( G tr ) between the two solvents (Equation 1).
o/w

G o/w
tr
= - 2.303 RT logP (Equation 1)

Lipophilicity reflects the complex interplay between the intermolecular forces that dictate the differential solvation
in the aqueous and organic phases. Accordingly, it can be factorized in terms of selected physicochemical properties
of the compound that may be relevant for the preferential solvation in aqueous and nonaqueous solvents, as shown
in Equation 2 [21], and references therein.

logP = vV -  + I + IE (Equation 2)

where v is a constant, V is the molar volume, which encompasses the ability of the solute to elicit nonpolar
interactions,  is related to the polarity of the compound, and finally I and IE accounts for the solute capacity
to form ionic interactions, which favor partitioning into the aqueous phase, and for the contribution due to
intramolecular effects, respectively.
Let us note that lipophilicity and hydrophobicity, which are often used as equivalent concepts, are not strictly
synonymous, the latter being in fact one of the contributions to molecular lipophilicity [22]. Thus, while hydropho-
bicity can be defined as the tendency of nonpolar groups of a molecule to aggregate in order to minimize the
unfavorable exposition to the surrounding polar (water) solvent, lipophilicity is a measure of the affinity of the
molecule for the nonpolar solvent in a biphasic system constituted by a polar and a nonpolar solvent.
Lipophilicity affects a number of pharmacokinetic parameters (Figure 1). Low lipophilicity is responsible of high
aqueous solubility, which is a key factor for drug-likeness, but an excessively low lipophilicity could compromise
the ability of the drug to achieve the biological target. On the opposite site, highly soluble compounds possess poor
permeability through biological membranes, limiting absorption along the gastrointestinal tract or the transport
across the blood–brain barrier. Therefore, optimal requirements for efficient solubility and permeability properties

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 Lipophilicity in drug design: an overview of lipophilicity descriptors in 3D-QSAR studies Review

Drug disposition

Absorption Distribution Metabolism Excretion

Solubility Permeability Enzyme Chemical

(bloodstream (passive, active) metabolism reactivity
concentration)
- Phase I
- Phase II
Protein/target
interaction
(drug potency)

- + - -

Lipophilicity

Figure 1. Schematic representation of the central role of lipophilicity in drug potency and pharmacokinetics profile.
Direct (+) and inverse (-) correlation of lipophilicity with each of the main steps of ADME process are also highlighted.

are inevitably enclosed in a very narrow range of lipophilicity. Another key aspect for drug-likeness is bioavailability,
which is inversely correlated to low first-pass clearance. Once again, lipophilicity is crucial since high lipophilicity
is associated with high clearance and low metabolic stability. Overall, a careful handling of lipophilicity is required
to optimize compound availability at the biological target.
On the other hand, lipophilicity has rarely been used as the primary descriptor in ligand–receptor recognition.
Indeed, following the IUPAC recommendation for the definition of a pharmacophore, it is defined as “the ensemble
of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological
target structure” [8]. This definition hides the key role played by (de)solvation in the recognition and binding of
a drug-like compound to its macromolecular target [23], especially keeping in mind that the maximal achievable
affinity that can be attained for target binding sites is largely influenced by nonpolar desolvation [24]. This is
consistent with the concept that favorable drug binding is largely driven not only by the global lipophilicity of a
compound, but more importantly by the spatial distribution of polar and apolar regions along the chemical skeleton.
Thus, while apolar regions determine the binding affinity with complementary lipophilic regions of the binding
site, polar interactions would provide ‘anchor points’ contributing to ligand specificity and/or directionality in the
binding pocket, as well as to modulate binding kinetics of the ligand [25–30].
Taken together, these data suggest that a concomitant optimization of both pharmacokinetic profile and drug
potency have to be done to obtain successful drug products. This is encoded in the concept of lipophilicity efficiency
(LipE), which provides a metric that normalizes the potency (generally measured as Ki or IC50 ) of the ligand against
a protein target for the lipophilicity of the compound [31–33]. This is achieved by substracting the logP (or the
distribution coefficient for ionizable molecules, logD) from the negative logarithm of the potency (Equation 3).

lipE =  log(potency)  logP (Equation 3)

Lipophilicity efficiency can be useful to provide guidelines to study the simultaneous effects exerted by structural
changes on potency and lipophilicity, which is central for drug design and lead optimization programs, thus giving
support to the formulation of the ‘lipophilic pharmacophore’ concept.

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Review Ginex, Vazquez, Gilbert, Herrero & Luque

From empirical fragment/atom-based approaches to 3D structure-based methods to estimate

lipophilicity
Numerous efforts have been done to assess lipophilicity by means of experimental methods [34–36]. Similarly, a
plethora of computational approaches for estimating logP have also been developed [37–42]. We limit ourselves to
remark selected fundamental concepts, while the reader is addressed to the previously quoted reviews for detailed
comparative analysis.
Within the framework of substructure-based methods for logP estimation, fragmental and atom-based techniques
follow a general additive scheme as shown in Equation 4,

 a i f i + j=1 b j Fj
n m
logP = i=1 (Equation 4)

where logP is the sum of the weighted (ai ) contribution of each fragment/atom (fi ) and a correction factor (bj Fj ).
Fragmental methods are illustrated by the work of Leo, Hansch and Elkins [43] as well as Nys and Rekker [44]. The
former relies on the concept of substituent constant, which encodes the lipophilicity contribution of a chemical
group or atom when it replaces a hydrogen atom in a reference compound, and the theoretical estimation of logPo/w
follows an additivity scheme, named cLOGP. This method permits to extrapolate the partition coefficients starting
from a list of experimentally fitted fragmental contributions to lipophilicity. An arbitrary set of interfragmental
rules was then used to compile a database library of fragment-weighted lipophilicity contributions. On the other
hand, Nys and Rekker [44] introduced the concept of hydrophobic fragmental constant (f), which represents the
lipophilicity contribution of a constituent part of a structure to the total lipophilicity of a given compound.
Fragments range from atoms to heterocyclic rings, so that functional groups with direct contribution to resonance
interactions were left intact, and are differentitated upon linkage to aliphatic and aromatic structures. The differences

between experimental logP and the additive value estimated from the f approach was accounted for by correction
rules, reflecting factors such as the presence of vicinal electronegative centers in the chemical structure, aromatic
condensation, cross-conjugation or hydrogen-bonding [45].
An example of atom-based partitioning strategy was undertaken by Ghose and Crippen, who developed a
procedure that combines lipophilicity contributions at an atomic level leading to the ALOGP method. This
method encompassed a list of 120 atom types for carbon, hydrogen, oxygen, nitrogen, sulfur and halogens [46–48].
An alternative strategy is the XLOGP method [49], which is based on the summation of atomic contributions
derived from experimental lipophilicity data of 1831 organic molecules, and includes correction factors for some
intramolecular interactions.
In the last decades, the evolution of computer performances enabled the development of whole molecule-based
strategies to predict the lipophilicity by taking into account the 3D-structure of compounds, and thus the effect
of molecular conformation. Among all the available techniques, the molecular lipophilicity potential (MLP) [50]
offers an empirical quantitative 3D-description of the lipophilicity potential from all the molecular fragments on
the surrounding space of a compound. The MLP approach is then intended to model the lipophilic interactions
between ligand and receptor as noted in Equation 5,

MLPK =  i=1 Fi f(d i k )

N
(Equation 5)

where Fi is the lipophilic fragmental contribution and f(dik ) is a distance function which depends on the
separation between a given fragment (i) and any point on the molecular surface or volume (k).
Molecular fields derived from the MLP potential have found a wide range of pharmaceutical applications,
including the prediction of skin permeation and distribution of new chemical entities [51], modeling of peptides
and proteins [52,53], and structure–activity relationships studies [54].
The Hydrophobic INTeraction (HINT) method represents an alternative, promising strategy for the study of
lipophilicity in biomolecular interactions [55,56]. This method exploits a scale of hydrophobic fragments constants
at the atomic level by means of an adaptation of the CLOGP method, which are then used to evaluate a pairwise

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 Lipophilicity in drug design: an overview of lipophilicity descriptors in 3D-QSAR studies Review

interaction energy term (bij ) between atoms i and j in the interacting partners according to Equation 6,

bij = a i Si a jS j Tij R ij + rij (Equation 6)

where ai and Si are respectively the hydrophobic constant and the accessible surface area of the atom i, Tij is a
logic function describing the character of interacting pairs (attraction or repulsion), and Rij and rij denote functions
of the distance between atoms i and j, the former following an exponential form and the latter a Lennard–Jones
implementation.
Equation 5 encodes the formalism of the ‘natural’ HINT force-field, which has been used to explore a variety of
applications in ligand–protein and protein–protein interactions [57–61].
Other approaches have relied on molecular properties derived from quantum mechanical treatments of molecules.
An early attempt is the work by Roger and Cammarata [62,63], who related the logP of aromatic compounds with
the charge density of both π and σ electron frameworks and the induced polarization. In a distinct approach, the
BLOGP method relied on semiempirical AM1 calculations to derive geometrical and quantum chemical descriptors
for the prediction of logP [64,65]. In a similar approach, Clark and coworkers performed AM1 and PM3 calculations
to derive a series of descriptors, including electrostatic potentials, total dipole moments, mean polarizabilities,
surfaces, volumes and charges, which were used in the prediction of partition coefficients [66,67].
These efforts can also be exemplified with the concept of heuristic MLP [68,69]. In this approach, the
lipophilic/hydrophilic features of a compound are determined from the analysis of the electrostatic potential
computed at the molecular surface. To this end, a dimensionless distance-dependent screening function is used to
compare the local electron density at the surface of a given atom with the electrostatic potential generated on the
rest of atoms. The screening function, which was derived from statistical mechanical treatment of polar solvent
molecules as dipoles, accounts for the influence exerted by the atomic descriptors of the electrostatic potential from
surrounding atoms. Ultimately, such a comparison leads to the definition of an atomic lipophilicity index, which
can adopt positive or negative values, reflecting the lipophilic and hydrophilic nature, respectively, of such an atom.
Finally, a distinct approximation comes from the usage of solute–solvent correlation functions derived by using the
reference interaction site model (RISM) as descriptors for QSAR studies. By using a classical statistical mechanics-
based solvent model combined with machine learning, 1D solute–solvent correlation functions were used to predict
Caco-2 cell permeabilities [70]. As an extension of this approach, Gussregen et al. proposed the Comparative Analysis
of 3D-RISM Maps (CARMa) methodology [71]. In this computational strategy, the classical electrostatic and steric
fields generally used in CoMFA are replaced by solute–solvent distribution functions determined from 3D-RISM
computations, which are subsequently treated as descriptors to perform QSAR analysis. The method was validated
using a set of serine protease inhibitors as a test system.
Even though CARMa uses a statistical mechanics solvent model, the electrostatic and steric effects implemented
in CoMFA cannot be directly captured. This issue has been recently addressed by solving 3D-RISM equations for a
solvent comprising CoMFA probes in aqueous solution, this extension being referred to as CARMa (electrolyte) [72].
The analysis performed for six protein–ligand systems reveals a small but consistent increase in prediction accuracy
compared with CoMFA.

Lipophilicity from QM continuum solvation methods

More elaborate methods for estimating the partition coefficients have been proposed in the framework of Quantum
Mechanical (QM)-based continuum solvation models [73,74], which were developed with the aim of predicting the
solvation free energy of solutes treating the solvent as a continuum polarizable medium. In spite of this rather
crude approximation, these methods have proved to be a promising strategy that combines well established physical
formalisms, a straightforward mathematical implementation and a reduced computational cost, while predicting
solvation free energies of (bio)organic compounds with chemical accuracy after a careful parameterization against
experimental data [75–77]. Since a broad review of these formalisms and their applications exceeds the aim of this
review, we limit ourselves to stress a selected set of recent studies addressing the potential impact of QM-based
continuum methods in drug design.

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COSMO & COSMO-RS-based approaches

In this context, the Continuum Solvation Model for Real Solvents (COSMO-RS) has been recently utilized to
evaluate the similarity between molecules within the so-called COSMOsim method [78]. This method relies on the
conductor-like screening model (COSMO) calculations to derive the so-called σ-profile of a given compound. The
σ-profile collects the set of polarization charge densities generated on the surface patches of the molecule immersed
in the solvent, which is treated as an ideal conductor. The 1D histogram distribution of the σ values for the
whole set of surface elements enclosed in the molecular surface gives rise to a characteristic signature of the solute,
which can be used to measure a σ-profile-based similarity between compounds with application for the detection
of bio-isosteric fragments or molecules. In order to enhance the computational efficiency, the σ-profile of a new
compound can be replaced with a composition of partial σ-profiles taken from similar fragments of precalculated
molecules stored in a database using COSMOfrag [79].
Since the σ-profile does not contain information about the spatial distribution of the polarization charge density,
COSMOsim3D has been recently proposed to alleviate this limitation [80]. To this end, COSMOsim3D projects the
surface charge density of each surface segment onto a regular 3D grid, so that each point of the grid has an associated
local σ-profile. In other words, instead of generating a single 1D σ-profile for the entire molecule, COSMOsim3D
creates a local 1D σ-profile at each position of a regular 3D grid. This process leads to a 4D histogram defined
by the three Cartesian dimensions of the grid point and the local σ-profile as the fourth dimension. If calculated
for two molecules, this strategy can be ultimately used to estimate their overall similarity. Furthermore, these local
σ-profiles have been also used to generate molecular interactions fields for 3D-QSAR studies [81].

Fragmental lipophilicity model from the Miertus–Scrocco–Tomasi method: the Hyphar approach
The Miertus–Scrocco–Tomasi (MST) solvation model has been used to develop 3D-distribution patterns of
lipophilicity, which in turn have been exploited in predicting molecular overlays and 3D-QSAR studies [82,83]. The
MST model is a parametrized version of the polarizable continuum model developed by Tomasi and coworkers [84,85]
at both semiempirical, Hartree–Fock and B3LYP levels [86–89] (for a review see [90]). From the solvation free energies
in water and n-octanol, one can derive the n-octanol/water partition coefficient (Equation 1), which is a property
of the whole molecule. Nevertheless, by decomposing the solvation free energy into atomic contributions, one can
obtain the 3D profile of lipophilicity from the corresponding atomic contributions to the logP. For a molecule (M)
containing N atoms, this is achieved by decomposing the logP (or the corresponding transfer free energy, G tr,M )
o/w

into electrostatic (logPele,i ), cavitation (logPcav,i ) and van der Waals (logPvw,i ) components, which can be derived
from the polar ( G ele,i ) and nonpolar ( G cav,i’G vW,i ) contributions to the solvation free energy (Equations 7
o/w o/w o/w

& 8).

 =  i=1 (G o/w

N N
G o/w
tr,M
= i=1
G o/w
tr,i ele,i
+G o/w
cav,i
+G o/w
vW,i (Equation 7)

 logPi =  i=1 (logP ele,i + logPcav,i + logPvW,i )

N N
logPM = i=1 (Equation 8)

Partitioning of the electrostatic term into atomic contributions can be made resorting to a perturbation ap-
proximation of the coupling between the solute charge distribution and the solvent reaction field [91], leading to
Equation 9,

1 qk w q1o
 
o/w o k L
logPele,i = ¨ =1 - =1 ¤o (Equation 9)
2 k ki w
rk - r I Ii o
r1 - r

where  o is the solute wave function in the gas phase, and K and L stand for the total number of reaction field
w o
charges in water ( qk ) and n-octanol ( qi ), located at positions rkw and ri o .

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The atomic decomposition of the cavitation and van der Waals terms takes advantage of the linear dependence
with the solvent-exposed surface of the atoms in the molecule (Equations 10 & 11).

Si
= i = 1
N
o/w
logPcav,i G o/w
P,i (Equation 10)
ST

=  i = 1 Si 
o/w N o
/w
logPvW,i (Equation 11)

where G p,i =G P,i - G P,i , G P,i being the cavitation free energy of atom i,  =  -  , with i
o/w W o o/w w o

being the atomic surface tension and Si denotes the contribution of atom i to the total molecular surface (ST ).
In contrast to the COSMO-RS-based approaches, which rely on the concept of σ-profile (see above), the MST-
derived applications use the atomic contributions to the thermodynamic components of the differential solvation
free energy in water and n-octanol, which are encoded under the partition coefficient between these two solvents.
Accordingly, they take into account the effect of specific chemical features of the molecule, such as the existence of
specific tautomers or conformational species, or the formation of specific intramolecular interactions (i.e., hydrogen
bond), in the computation of the 3D-distribution pattern of molecular lipophilicity.
These patterns have been exploited to predict the chemical similarity between compounds [92]. By using the MST-
o/w o/w
based hydrophobic descriptors logPeles,i and logPcav,i , a computational procedure has been proposed to identify
the molecular overlay that maximizes the lipophilic similarity. To this end, molecular similarity was achieved
by comparing the hydrophobic fields generated by the molecules, which were prealigned following multipole
expansions of the atomic lipophilic contributions. On the other hand, simple descriptors of the hydrogen-bond
(HB) donor/acceptor character of atoms were used to complement the information about the chemical nature
of polar atoms in a molecule (briefly, the current implementation assigns an arbitrary value of +1 to hydrogen
atoms in HB donors, and -1 to N and O atoms that may act as acceptors). This choice obeys to the fact that
the polar nature of hydrophilic groups cannot distinguish the HB donor/acceptor character, as this information is
o/w
not implicitly encoded by the logPele,i term. Hydrophobic and HB properties are then projected into a 3D grid
using the exponential function (Equation 12) implemented in CoMSiA [15], and then compared by means of the
Tanimoto coefficient.
2

p q =  i=1 w i e
N -–riq
(Equation 12)

The method was implemented in PharmScreen software [83,93] and was successfully used to evaluate the molecular
overlay for a collection of 121 molecular systems compiled by AstraZeneca, denoted as the AstraZeneca Overlays
Validation Test Set [94]. This set contains molecular overlays experimentally characterized for 119 targets, which were
grouped in four categories according to the expected difficulty in predicting the experimental overlay: easy, moderate,
hard and unfeasible. The results pointed out that correct overlays were predicted for 94% (easy), 79% (moderate) and
54% (hard) of the cases. Moreover, the overall performance obtained from classical electrostatic/steric descriptors
and from Hyphar ones was fairly similar for easy and moderate subsets, but the accuracy obtained with Hyphar
for the subset of hard cases exceeded the performance obtained with electrostatic/steric properties. Finally, it was
found that the similar performance of Hyphar and electrostatic/steric descriptors does not imply that they lead
to identical overlays. Rather, the analysis of the predicted poses revealed that the degree of identity in molecular
overlays was reduced with the increase in the difficulty of the target. Overall, these findings point out that Hyphar
descriptors may be a valuable alternative for molecule superposition and VS of chemical libraries, especially for
targets that may be challenging for predictive molecular similarity techniques.
On the other hand, the atom-centered MST-derived hydrophobic contributions have also been used as physic-
ochemical descriptors to derive 3D-QSAR models using PharmQSAR [82]. MST/IEFPCM calculations were
performed for five sets of compounds, including dopamine D2/D4 receptor antagonists, antifungal chromanones,
glycogen synthase kinase-3 inhibitors, cruzain inhibitors and thermolysin inhibitors. The compounds in these

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sets covered a wide range of variance in selected physicochemical properties (molecular weight, hydrogen-bond
donor/acceptor, clogP and number of rotatable bonds). The 3D-QSAR models obtained with the hydrophobic
pharmacophore (HyPhar) were found to have a predictive accuracy comparable to standard CoMFA and CoMSiA
techniques. Moreover, Hyphar descriptors were also valuable to discriminate the selectivity of compounds acting
as inhibitors of thrombin, trypsin and factor Xa [83].
Overall, these findings support the usefulness of the MST-derived lipophilic descriptors as a valuable alternative
to electrostatic/steric properties to carry out VS of chemical libraries for molecular similarity, as well as to derive 3D-
lipophilic pharmacophores, thus providing valuable complementary information to gain insight into the molecular
determinants of bioactivity.

A comparative analysis between Hyphar & electrostatic/steric properties

The strength of Hyphar descriptors in 3D-QSAR studies may be attributed to two major features. First, the
concept of lipophilicity is very intuitive and widely accepted in medicinal chemistry. Second, the partitioning of
lipophilicity, which reflects a property of the whole molecule, into atomic or fragmental contributions permits to
obtain a graphical representation of the distribution pattern of polar and apolar regions adapted to the 3D-structure
of a given compound. In turn, this paves the way to rationalize the recognition between a small compound and
its macromolecular target from the complementarity between hydrophilic and lipophilic groups of the ligand and
the polar and apolar nature of the side chains of residues that shape the binding pocket. As an additional remark,
let us note that resorting to Hyphar descriptors benefits from the accurate description of the molecular charge
distribution that can be attained by QM methods, which may take into account the influence arising from the
chemical features of the bioactive compound, such as the ionization state, the preference for a tautomeric species,
and the adoption of a given conformational state representative of the binding mode of the ligand.
Given the novelty of MST-based atomic lipophilicity contributions, it is nevertheless necessary to explore their
suitability for 3D-QSAR studies. In this context, this section reports the results of a comparative analysis performed
to calibrate the performance of Hyphar descriptors through comparison with electrostatic/steric ones. This analysis
has been carried out using the comprehensive benchmark dataset compiled by Sutherland and coworkers [95], which
comprises 113 ACE inhibitors, 111 AChE inhibitors, 147 ligands for BZR, 282 COX-2 inhibitors, 361 DHFR
inhibitors, 66 GPB inhibitors, 74 THER inhibitors and 87 THR inhibitors.
Accordingly, the CoMFA/CoMSiA results reported in [95] were compared with the 3D-QSAR models obtained
using Hyphar descriptors, which combine both ‘polar’ (logPele,i ) and ‘non-polar’ (logPcav,i ) hydrophobic contributions
(see above). To this end, the atomic electrostatic and nonelectrostatic components of the lipophilicity were used
to generate the molecular fields through projection into a grid that encloses the set of aligned compounds using a
similarity index function (see [82] for further details). For the sake of comparison, the original molecular geometries
and protonation states of compounds were kept in this study. All the details about models generation, grid
dimensions and points, training/test sets, and related activity ranges for the eight sets compiled by Sutherland are
reported in Supplementary Material (Supplementary Tables 1–3). Only for the THERM dataset partition between
training and test sets was made as indicated in [15].
As a preliminary step, the effect of the QM method selected to derive the hydrophobic contributions on the
performance of the 3D-QSAR Hyphar models was evaluated for a subset of four systems (D2 inhibitors, antifungal
chromanones, GSK3-β and cruzain inhibitors) taken from our previous study [82]. To this end, Hyphar descriptors
were derived from continuum computations performed with the MST version parametrized for the semiempirical
RM1 method [96], and alternatively with the version parametrized at the B3LYP/6-31G(d) level [89]. Comparison
of the statistical parameters obtained for the subset of training and test compounds defined for each molecular
system is shown in Table 1.
The results reveal that there is large resemblance in the overall performance of the 3D-QSAR models obtained
from MST/RM1 and MST/B3LYP Hyphar descriptors for all datasets. This finding is remarkable, since 3D-QSAR
models derived from the RM1 hydrophobic descriptors compare well with the performance obtained at the B3LYP
level, but at a much lower computational cost, making the usage of semiempirical methods highly attractive for the
study of large libraries of drug-like compounds. Accordingly, the computationally less demanding RM1 method
seems to be a promising choice for 3D-QSAR studies with Hyphar parameters.
On the basis of these results, the benchmark dataset reported by Sutherland and coworkers [95] was examined using
the MST/RM1 Hyphar descriptors. The 3D-QSAR Hyphar models were compared with the CoMFA/CoMSIA
results reported in [95], which were obtained by using electrostatic potential-fitted charges at the MNDO level, but

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 Lipophilicity in drug design: an overview of lipophilicity descriptors in 3D-QSAR studies Review

Table 1. Statistical parameters of the 3D-QSAR HyPhar models obtained from Miertus–Scrocco–Tomasi/B3LYP and
Miertus–Scrocco–Tomasi/RM1 calculations for the four sets of compounds.†
System Training set Test set Nc Field (%)
r2 q2 S Spress r2 S Elec Nonelec
D2
MST/B3LYP 0.94 0.77 0.31 0.60 0.78 0.57 3 68.6 31.4
MST/RM1 0.93 0.74 0.28 0.65 0.71 0.63 3 70.9 29.1
Chromanones
MST/B3LYP 0.77 0.51 0.49 0.29 0.81 0.20 3 34.3 65.7
MST/RM1 0.76 0.42 0.51 0.32 0.66 0.82 3 42.1 57.9
GSK3
MST/B3LYP 0.91 0.80 0.12 0.19 0.79 0.21 3 54.5 45.5
MST/RM1 0.91 0.82 0.30 0.18 0.79 0.21 5 64.7 35.3
Cruzain
MST/B3LYP 0.81 0.50 0.31 0.51 0.69 0.47 2 53.0 47.0
MST/RM1 0.91 0.65 0.31 0.44 0.70 0.46 3 58.4 41.6
† See [91] for a proper description of the molecular sets. Nc denotes the number of PLS components in the best 3D-QSAR model, and the terms Elec and Nonelec stand for the fraction

(in percentage) of electrostatic (logPele,i ) and nonelectrostatic (logPcav,i ) hydrophobic contributions to the final model.
MST: Miertus–Scrocco–Tomasi.

for the THER set, where Gasteiger–Marsili charges were used. For the sake of comparison, an additional model,
denoted CoMFA (RM1), which exploits RM1 electrostatic-potential fitted partial charges in conjunction with an
steric field obtained from the Lennard–Jones potential with a positively charged C.3 atom probe, was also examined.
This model, therefore, is intended to explore the efficiency of RM1-based partial charges in defining electrostatic
features of molecules at the atomic level.
Table 2 shows the statistical parameters of the 3D-QSAR models. In general, similar performances were obtained
for the different 3D-QSAR models determined for molecules in the training test included in a given system, as
noted in the large resemblance between the statistical values of the regression (r2 ) and cross-validation (q2 ) models.
The same trend can be observed for the test set compounds, although a small improvement was found for CoMFA
(RM1) and Hyphar models in GPB and THERM systems compared with reference CoMFA/CoMSiA models. In
addition, a higher level of accuracy was also achieved by the models derived from RM1 calculations since the number
of outliers in the test set was lower than in classical CoMFA/CoMSIA (Supplementary Material, Supplementary
Table 4). On the other hand, both BZR and COX2 were confirmed to be challenging systems for QSAR modeling,
as already noted by Sutherland and coworkers [95]. For instance, in case of COX2, part of the reason for the poor
predictive behavior may probably be ascribed to the fact that training and test set cover different ranges of in the
property space.
The predictive performance of the models was also examined by analyzing their capacity to discriminate between
active and inactive compounds. To this end, for each molecular system the compounds in the test set were
ranked according to their experimental potency: ‘active/positive’ (P) and ‘inactive/negative’ (N) were categorized
by applying a threshold value of 6.0 (in pIC50 /pKi units). Then, test set compounds with a predicted pIC50 /pKi
value larger than the threshold value were considered ‘actives/positives’ (TP), whereas compounds with a predicted
pIC50 /pKi value lower than the threshold were considered ‘inactives/negatives’ (TN). For each molecular system,
the number of P, N, TP and TN compounds, as well as false positives (FP) and false negatives (FN) are compiled
in Supplementary Material (Supplementary Table 5). In turn, these values were used to identify correctly negative
(specificity or TNR; in green in Figure 2) and positive (sensitivity or TPR; in blue in Figure 2) compounds, and to
reduce the false negative rate (‘fall-out’ or FPR; in red in Figure 2) by applying Equations. 13-15.

TN TN
Specificity(TNR) = = (Equation 13)
N (TN+FP)

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Table 2. Statistical parameters obtained for CoMFA and CoMSiA models reported with the results determined by using
COMFA (RM1) and Hyphar models in this study for the eight molecular systems (ACE, AChE, BZR, COX2, DHFR, GPB, THERM
and THR).†
System Training set Test set Nc* Field (%)
r2 q2 S Spress r2 S Ele N-Ele HB
ACE‡
CoMFA 0.80 0.68 1.04 – 0.49/0.55 1.54/1.47 3 – – –
CoMSiA 0.76 0.65 1.15 – 0.52/0.58 1.48/1.41 3 – – –
CoMFA (RM1) 0.82 0.67 0.42 1.37 0.54/0.61 1.45/1.32 3 29.4 70.6 –
Hyphar 0.75 0.64 0.51 1.43 0.42/0.62 1.62/1.35 2 28.8 53.5 17.7
AChE
CoMFA 0.88 0.52 0.41 – 0.47/0.56 0.95/0.87 5 – – –
CoMSiA 0.86 0.48 0.45 – 0.44/0.60 0.98/0.81 6 – – –
CoMFA (RM1) 0.90 0.54 0.32 0.85 0.35/0.52 1.07/0.86 6 20.0 80.0 –
Hyphar 0.76 0.45 0.50 0.92 0.65 0.78 4 64.1 18.7 17.2
BZR
CoMFA 0.61 0.32 0.41 – 0.00/0.18 0.97/0.81 3 – – –
CoMSiA 0.62 0.41 0.41 – 0.08/0.30 0.93/0.75 3 – – –
CoMFA (RM1) 0.60 0.36 0.64 0.53 0.21/0.21 0.81/0.80 3 30.5 69.5 –
Hyphar 0.67 0.37 0.58 0.54 0.00/0.02 0.91/0.86 6 48.8 16.7 34.5
COX2
CoMFA 0.70 0.49 0.56 – 0.29/0.37 1.24/1.09 5 – – –
CoMSIA 0.69 0.43 0.56 – 0.03/0.22 1.44/1.20 6 – – –
CoMFA (RM1) 0.74 0.51 0.52 0.72 0.19/0.34 1.20/1.07 5 28.6 71.4 –
Hyphar 0.60 0.52 0.63 0.71 0.26/0.40 1.15/0.99 3 85.4 4.3 10.3
DHFR
CoMFA 0.79 0.65 0.59 – 0.59/0.70 0.89/0.73 5 – – –
CoMSiA 0.76 0.63 0.62 – 0.52/0.63 0.96/0.81 5 – – –
RM1 CoMFA 0.81 0.67 0.44 0.73 0.42/0.55 1.04/0.91 4 17.7 82.3 –
Hyphar 0.72 0.63 0.53 0.78 0.53/0.56 0.94/0.89 5 36.2 38.8 25.0
GPB
CoMFA 0.84 0.42 0.43 – 0.42/0.37 0.94/0.70 4 – – –
CoMSiA 0.78 0.43 0.50 – 0.46/0.34 0.90/0.82 4 – – –
CoMFA (RM1) 0.88 0.43 0.36 0.85 0.51 0.89 4 24.4 75.6 –
Hyphar 0.83 0.54 0.42 0.75 0.71 0.68 3 52.0 2.7 45.3
THERM
CoMFA 0.94 0.51 0.55 1.54 0.60 1.26 7 – – –
CoMSiA 0.85 0.54 0.73 – 0.36/0.46 1.87/1.60 6 – – –
CoMFA (RM1) 0.90 0.46 0.33 1.57 0.51/0.66 1.39/1.18 5 25.5 74.5 –
Hyphar 0.84 0.49 0.41 1.51 0.67 1.13 4 37.9 25.5 36.6
THR¶
CoMFA 0.86 0.59 0.36 – 0.54/0.73 1.59/0.56 4 – – –
CoMSiA 0.88 0.62 0.34 – 0.55/0.62 0.76/0.66 5 – – –
CoMFA (RM1) 0.89 0.59 0.33 0.64 0.45/0.58 0.86/0.82 5 16.0 84.0 –
Hyphar 0.87 0.64 0.37 0.59 0.53/0.56 0.79/0.74 4 37.5 41.7 20.8
† For 2
test sets compounds, statistical parameters (r and S) with (left) and without (right) outliers (i.e., compounds with residuals higher than 2.5-fold the standard deviation) are indicated.
The number of outliers for each system is reported in Supplementary Material (Supplementary Table 4).
‡ mol0088 (original file name mol 17) was excluded because it contains iodine atom.
¶ mol0088 (original file name 82) was excluded due to problems with the input geometry.

ACE: 113 angiotensin converting enzyme; AChE : 111acetylcholinesterase;BZR : 147 ligands for benzodiazepine receptors; COX-2: 282 cyclooxygenase-2; DHFR : 361 dihydrofolatereductase;
GPB: 66 glycogen phosphorylase b; THER: 74 thermolysin ; THR: 87 thrombine.

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 Lipophilicity in drug design: an overview of lipophilicity descriptors in 3D-QSAR studies Review

1.0

0.7

0.5

0.2

0.0
ACE

AchE

BZR

COX2

DHFR

GPB

THERM

THR
Figure 2. Specificity (in green), sensitivity (in blue) and fall-out (in red) for RM1 CoMFA (left) and H2 (right) models
the test sets of the eight systems.

TP TP
Sensitivity (TPR) = = (Equation 14)
P (TP+FN)

FP FP
Fall - out (FPR) = = = 1 - TNR (Equation 15)
N (FP+TN)

These parameters, which can vary from 0 to 1, can be considered a measure of the predictive performance of
the model. According to this classification, a model can be considered good if it has high specificity/sensitivity
and low fall-out values. Nevertheless, this analysis requires a balanced partition of active and inactive compounds
in the set of compounds, a requirement that is not fulfilled in the case of BZR and GPB systems, since only one
inactive and one active compound are present in these two sets, respectively. Accordingly, the results obtained for
BZR and GPB should be excluded from the analysis. For the rest of molecular systems, both CoMFA (RM1) and
Hyphar models exhibit generally similar trends (Figure 2). The Hyphar model has a slightly better performance
in sensitivity/specificity and fall-out values for AchE, THERM and THR systems, whereas the opposite trend is
found for CoMFA (RM1) in ACE and COX2.
Finally, the ability of CoMFA (RM1) and Hyphar models to rank the compounds according to their potency was
also examined (Figure 3). To this end, the Spearman (Rs) coefficient for the first (Q1; in green), second (Q2; in blue)
and third (Q3; in red) quartiles, which would encompass molecules with highest, medium and low activity/affinity,
were determined for the test set compounds in each system. Although there is a notable resemblance in the general
trends obtained for CoMFA (RM1) and Hyphar models, slightly better performances (higher Rs values) are observed
for Hyphar models, especially for compounds of higher activity/affinity (Q1/Q2), whereas the differences are less
pronounced for compounds in Q3, probably due to the larger noise associated with the biological activity low
active compounds.
Overall, the results obained for the benchmark systems reveal that the Hyphar descriptors yield 3D-QSAR
models with an overall performance that compares with the results obtained using standard CoMFA/CoMSiA.
Hyphar models also seem to be more effective in locating (high sensibility) and ranking (high Rs) true positives,
especially in regions of high and medium activity/affinity.

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Review Ginex, Vazquez, Gilbert, Herrero & Luque

1.0

0.8

0.5

0.3

0.0
ACE

AchE

BZR

COX2

DHFR

GPB

THERM

THR
-0.3

-0.5

-0.8

-1.0

Figure 3. Spearman (Rs) coefficients for the first (Q1; in green), the second (Q2; in blue) and the third (Q3; in red)
quartiles for RM1 CoMFA (left) and H2 (right) models.

Final consideration & perspective

The concept of pharmacophore is essential to disclose the key features that dictate the interaction between ligand
and receptor. Hence, it represents an important tool to identify guidelines valuable in computer-aided drug
design, covering a variety of applications such as molecular similarity, VS, ligand optimization, scaffold hopping,
as well as modeling of ADME(T) properties and target identification. The descriptive and predictive power
of pharmacophores depends on the quality and adequacy of molecular properties used to disclose the hidden
relationship between activity and chemical structure. In the last decades, several strategies were developed to
derive descriptors capable of capturing the chemical features relevant for drug design, including the application of
descriptors derived from QM methods coupled to continuum solvation models.
Although fundamental for the activity of drug-like compounds, inclusion of lipophilicity as a major descriptor
has revealed more elusive, possibly due to the complexity of the chemical processes encompassed by this concept,
or the difficulty to find a rigorous formalism to reduce it to atomic contributions since lipophilicity reflects a
property of the whole molecule. In this context, it is worth stressing the efforts in deriving tools such as MLP [51]
and HINT [55,56], where the molecular lipophilicity was treated by means of empirical atomic contributions, and
hence enabling the analysis of the 3D-distribution of polar/apolar regions along the chemical scaffold to provide a
novel interpretation to the molecular determinants responsible of biological activity.
QM-based continuum solvation methods are a promising strategy for deriving 3D-descriptors, such as COSMO-
RS-based σ-profiles [78–81] or MST-derived 3D-lipophilicity patterns [82,83,92,97–99], which in turn may be exploited
in computer-aided drug design. The set of studies reported up to now for a variety of benchmark datasets,
covering both measurements of molecular similarity for aligned compound or the derivation of 3D-QSAR models,
are encouraging. In general, the statistical performance of these QM-based descriptors compares well with the
results obtained from classical approaches, generally combining electrostatic and steric fields, as illustrated in the
comparative analysis reported here for the sets of compounds considered by Sutherland and coworkers [95]. At least
in part, this may be due to the limitations of electrostatic/steric descriptors for describing enthalpy and entropy
contributions to the binding affinity. On the other hand, QM-based approaches permit to account directly for the
specific features of the bioactive species of the ligand, including effects attributable to ionization, tautomerism or
the specific conformation, which may be advantageous compared with generic descriptors derived from empirical
contributions. These computational approaches benefit from the usage of lipophilicity, a property widely used in
drug design, easy to interpret by medicinal chemists and linked to a physicochemical property that can be measured
experimentally. Through partitioning of the molecular lipophilicity into atomic contributions, novel fractional
models that account for the 3D-lipophilicity pattern of compounds can then be exploited in computer-assisted
drug design.

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 Lipophilicity in drug design: an overview of lipophilicity descriptors in 3D-QSAR studies Review

Overall, the analysis of structure–activity relationships in terms of the lipophilic/hydrophilic balance may provide
a useful signature to complement studies performed with electrostatic/steric properties. In this sense, the QM MST-
based hydrophobic descriptors are valuable in predicting molecular overlays and elucidating molecular similarity
patterns. The higher descriptive quality of these descriptors could thus offer interesting clues in searching for novel
bioactive compounds, especially for challenging targets.

Executive summary
• All biological and biochemical processes are driven by the general concept of host–guest complementarity.
Accordingly, an essential but effective description of the ‘guest’ is required for a successful prediction of ‘host’
recognition.
• The pharmacophore concept is a fundamental cornerstone in drug discovery, as it accounts for the common
interaction features of a group of compounds toward their target structure, playing a critical role in determining
the success of in silico techniques.
• Optimized descriptors able to model both pharmacokinetics and pharmacodynamics properties in drug design are
not easily achievable, and the use of suboptimal physicochemical parameters may be a more effective strategy.
• Besides the relevance in predicting ADME(T) properties, lipophilicity exerts a pivotal role in accounting for the
maximal achievable affinity that can be attained between ligand and receptor.
• The usage of lipophilicity descriptors may offer novel opportunities to disclose the underlying relationships
between chemical features and biological activity. In this context, the availability of refined version of QM-based
continuum solvation models may be an effective strategy for deriving novel descriptors well suited for drug
design.
• In 3D-QSAR studies, the Miertus–Scrocco–Tomasi-derived Hyphar descriptors have been shown to provide models
for structure–activity relationships with a predictive accuracy comparable to CoMFA/CoMSiA techniques based on
electrostatic/steric parameters.
• The Hyphar descriptors are also a valuable alternative for molecule superposition and virtual screening of
chemical libraries, especially for targets that may be challenging for predictive molecular similarity techniques.
• The availability of ‘polar’ and ‘non-polar’ fractional descriptors obtained from Miertus–Scrocco–Tomasi-based
continuum solvation models may be valuable to explore the molecular determinants of bioactivity, providing
complementary interpretations to classical descriptors in the rational design of novel compounds.

Acknowledgments
The authors acknowledge J Muñoz-Muriedas (GSK group, Stevenage, UK) for valuable comments and suggestions.

Financial & competing interests disclosure

The authors thank the Ministerio de Economı́a y Competitividad (MINECO: SAF2017-88107-R, DI-14-06634, MDM-2017-0767)
and the Generalitat de Catalunya (2017SGR1746, 2015-DI-052) for financial support. The Consorci de Serveis Universitaris de
Catalunya (CSUC) is acknowledged for computational resources (Molecular Recognition project). J Vazquez is fellowship from the
Generalitat de Catalunya. The authors have no other relevant affiliations or financial involvement with any organization or entity
with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those
disclosed.
No writing assistance was utilized in the production of this manuscript.

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