J Pharm Pharm Sci (www.cspsCanada.

org) 17(4) 532 - 540, 2014

To Be Drug or Prodrug: Structure-Property Exploratory Approach

Regarding Oral Bioavailability
Mariana C. F. C. B. Damioa; Kerly F. M. Pasqualotob; Michelle C. Pollic; Roberto Parise-Filhoa
a

Department of Pharmacy, School of Pharmaceutical Sciences, University of So Paulo, So Paulo, Brazil; bBiochemistry
and Biophysics Laboratory, Butantan Institute, So Paulo, Brazil; cDepartment of Pharmacy, So Francisco University,
Campinas, Brazil
Received, September 15, 2014; Revised, October 24, 2014; Accepted, October 30, 2014; Published, November 6, 2014

ABSTRACT - Purpose. Prodrug design is a strategy that can be used to adjust physicochemical properties of
drugs in order to overcome pharmacokinetic problems, such as poor oral bioavailability. However, Lipinskis
and Vebers rules predict whether compounds will have absorption problems even before the design of
prodrugs. In this context, our goal was to evaluate the molecular properties which most influenced the
absorption process of prodrugs compared to its precursor through exploratory data analysis approach.
Methods: A variety of prodrugs and respective precursors were randomly selected and classified by its
percentage of human intestinal absorption. Subsequently, different molecular properties were calculated and
hierarchical cluster analysis (HCA) and principal components analysis (PCA) were carried out.
Results: According to the findings, antiviral, anti-hypertensive, and antibiotic prodrugs exhibited higher
absorption levels than their respective precursors. Also, some relevant descriptors (molecular weight, MW,
routable bonds, rot_bonds, hydrogen bond acceptors, HBA_count and polar surface area, PSA), which are
included in Lipinskis and Vebers rules, influenced the separation process between prodrugs and drugs.
Furthermore, other molecular properties, such as polarizability () and molar refractivity (MR), were pointed
out. Conclusion: Lipinskis and Vebers rules proved to be important to design an orally administered drug but
other descriptors should be considered by medicinal chemists in the prodrug designing process.
This article is open to POST-PUBLICATION REVIEW. Registered readers (see For Readers) may
comment by clicking on ABSTRACT on the issues contents page.

Physicochemical properties are directly dependent

upon the chemical structure of compounds and play
important role in each phase. In this regard,
molecules which do not have suitable
physicochemical properties would not overcome
any of those three phases, limiting their use in
clinical practice (14). The main goal of
pharmaceutical industries, nowadays, is to discover
new, safe, effective, and orally administered
chemical entities. Despite some limitations
attributed to oral route, it has still remained as
preferential for drug administration (5) due to high
patient compliance, simple production conditions,
and low cost (6,7). However, the major problem

INTRODUCTION
The three phases of drug action, described by
Arins (1), relate dose to pharmacological effect
and are very well-known. In sequence, the
pharmaceutical phase corresponds to the release of
drug (active substance) from the dosage form, and
comprises all physical processes involved in the
disintegration of the form in which a compound was
administered as well as the dissolution of the active
substance in organic fluids (pharmaceutical
availability). The pharmacokinetic phase covers
processes involved in absorption, distribution,
protein
binding,
metabolism,
intracellular
penetration, transport through membranes and
through the blood-brain barrier, and renal excretion.
The pharmacodynamics phase comprises the drugtarget molecular interaction at the tissue site,
initiating and triggering a sequence of intrinsic
events finally resulting in the biological response.

Correspondence Authors: Roberto Parise-Filho, Department

of Pharmacy, School of Pharmaceutical Sciences, University of
So
Paulo,
So
Paulo,
SP
05508-000,
Brazil.
roberto.parise@usp.br; Kerly Pasqualoto, Biochemistry and
Biophysics Laboratory, Butantan Institute, So Paulo, SP
05503-900, Brazil. kerly.pasqualoto@butantan.gov.br

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related to the development of new orally

administered drugs is low oral bioavailability.
Hit to lead optimization processes, for
instance, are among molecular modification
strategies which structural changes are planned in
order to generate either more active analogues, or
temporarily inactive derivatives (prodrugs), which
could
improve
pharmacokinetic
and
pharmacodynamics profiles (810). Regarding
prodrug design strategy, or latentiation method, the
main purpose is to modify physicochemical
properties of drugs to reduce undesirable
pharmacokinetic features, but maintaining drugs
intrinsic activity. Thus, the drugs physicochemical
properties can be adjusted through a proper choice
of carrier groups in order to increase oral
absorption, for example (11,12).
Prior to the designing of a prodrug, virtual
and rational approaches have been applied in order
to predict molecular behavior and, then, reduce the
risk of failure in developing a new molecule. One of
these approaches is the Rule of Five (Ro5)
developed by Lipinski et al. (13), which generally
allows the prediction of drugs oral bioavailability.
This rule identifies descriptors based on intrinsic
and physicochemical properties, such as molecular
weight (MW), lipophilicity (ClogP), hydrogen bond
donors (HBD), and hydrogen bond acceptors
(HBA) (13,14). All together, these descriptors help
to infer whether the studied compounds might have,
or not, problems regarding absorption. Thus, Ro5
can be used as a rapid screening method to identify
poorly absorbed chemical entities. Drugs showing
physicochemical descriptors values within an
established range would have sufficient absorption
after oral administration, and consequently suitable
bioavailability. In general, high absorption rates for
a chemical entity can be achieved when the number
of HBD is less than 5, the number of HBA is less
than 10, MW is less than 500 Da, and ClogP is less
than 5 (15).
Subsequently, Ro5 was expanded by Veber et
al. (16), who have identified two other important
descriptors for an ideal oral bioavailability, such as
the number of rotatable bonds (rot_bonds) and polar
surface area (PSA). The number of rotatable bonds
must be less than or equal to 10. This descriptor is
related to molecular flexibility (degrees of
freedom), which reflects on the conformational
arrangement, considered as an important factor
regarding the passive transport throughout

membranes. Furthermore, the number of degrees of

freedom is quite related to the change of entropy
upon binding, which is an important factor
determining the binding affinity of compounds
toward their targets. In addition, Veber and coworkers (16) have also indicated compounds with
polar surface area (PSA) values less than or equal to
140 2 would have better oral bioavailability. In
this regard, chemical entities that violate Lipinkis
rules as well as Vebers expanded version could be
classified as excellent candidates for prodrugs
designing. Accordingly, prodrugs designed to
increase oral absorption should have the calculated
value for descriptors, such as ClogP, MW, HBD,
HBA, PSA and rot_bonds, within the ranges
previously established by Lipinski and Veber
(13,14,16).
Of note, other types of procedures,
considering molecular mechanics and quantum
mechanics approaches, have been applied in order
to investigate and predict drug/prodrug absorption
profiles (17). However, herein, the aim was to
evaluate the behavior of classical prodrugs
regarding the expanded Ro5 ranges, and identify the
differences between latent chemical entities and
respective precursors. In addition, based on an
exploratory analysis, the molecular properties
which had more influence on the prodrugs and
drugs differentiation process were detected and
correlated to pharmacokinetics profile.
METHODS
Drugs and Prodrugs Selection
The set of prodrugs (PRO) and parent drugs were
selected from reference Parise-Filho et al. (12).
Regarding the commercially available prodrugs,
those classified as classical prodrugs, which were
designed in order to improve bioavailability, were
randomly selected. A variety of therapeutic classes
was considered in this investigation, such as
antiviral, antibiotic, and anti-hypertensive drugs.
The molecules selected as antivirals were the
following: valacyclovir (VAL_PRO) and acyclovir
(ACY), famciclovir (FAM_PRO) and penciclovir
(PEN), tenofovir disoproxil (TN_PRO) and
tenofovir (TN), olsetamivir (OSEL_PRO) and
olsetamivir
carboxylate
(OSEL).
Also,
bacampicillin (AMP_PRO) and ampicillin (AMP),
cefuroxime axetil (CEFOX_PRO) and cefuroxime
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(CEFOX), cefetamet pivoxil (CEFT_PRO) and

cefetamet
(CEFT),
cefpodoxime
proxetil
(CEFP_PRO) and cefpodoxime (CEFP) were
chosen as antibiotic agents. Finally, among antihypertensive molecules we selected the following:
enalapril (ENA_PRO) and enalaprilate (ENA),
ramipril (RAM_PRO) and ramiprilate (RAM),
benazepril (BN_PRO) and benazeprilate (BN),
quinapril (QUI_PRO) and quinaprilate (QUI),
fosinopril (FOS_PRO) and fosinoprilate (FOS).
The percentage of human intestinal
absorption (% HIA) for selected prodrugs and
precursors was obtained from pharmacokinetic data
previously reported (1828) and well-known
databanks (2931). The classification based on %
HIA, previously reported by Zhao et al. (24), was
used to score the absorption profile of prodrugs and
precursors as high, moderate and low (see Table 1).
Calculation of Molecular
Exploratory Data Analysis

Properties

Table 1. Percentage values of human intestinal

absorption (% HIA) and score of absorption profile
Score of
HIA
absorption
(%)
profile*
Acyclovir (ACY)
16
Low
Valacyclovir (VAL_PRO)
55 Moderate
Penciclovir (PEN)
4
Low
Famciclovir (FAM_PRO)
77
High
Tenofovir (TN)
25
Low
Tenofovir disoproxil (TN_PRO)
40 Moderate
Oseltamivir carboxilate (OSEL)
4
Low
Oseltamivir (OSEL_PRO)
75
High
Enalaprilate (ENA)
10
Low
Enalapril (ENA_PRO)
71
High
Benazeprilate (BN)
3.8
Low
Benazepril (BN_PRO)
64 Moderate
Quinaprilate (QUI)
38 Moderate
Quinapril (QUI_PRO)
80
High
Ramiprilate (RAM)
5
Low
Ramipril (RAM_PRO)
60 Moderate
Fosinoprilate (FOS)
29
Low
Fosinopril (FOS_PRO)
36 Moderate
Ampicillin (AMP)
45 Moderate
Bacampicillin (AMP_PRO)
87
High
Cefuroxime (CEFOX)
5
Low
Cefuroxime axetil (CEFOX_PRO)
44 Moderate
Cefpodoxime (CEFP)
21
Low
Cefpodoxime proxetil (CEFP_PRO) 50 Moderate
Cefetamet (CEFT)
31
Low
Cefetamet pivoxil (CEFT_PRO)
50 Moderate
PRECURSORS/PRODRUGS

and

The structures of prodrugs and respective

precursors were retrieved from DrugBank version
4.1 (www.drugbank.ca) and molecular properties of
different nature were calculated using Marvin
5.10.3 (ChemAxon Ltd., 1998-2012), including
those considered in Linpiskis and Vebers rules.
Then, a table (X block) was generated which the
rows corresponded to samples or drugs investigated
(N = 26), and the columns to calculated molecular
properties (27 independent variables or descriptors).
This table (see Supplementary Material) was used
as input data to carry out the exploratory data
approach.
Exploratory data analysis comprised two
unsupervised methods: hierarchical cluster analysis
(HCA) and principal components analysis (PCA)
(32,33). HCA and PCA were carried out using
Pirouette 3.11 (Infometrix Inc., 1990-2003). An
autoscaling procedure was applied as a
preprocessing method in both analyses. The
complete linkage method and Euclidean distance
were considered in HCA. The distances between
samples or variables were calculated according to
Equation 1.

*Percent values of human intestinal absorption were

classified as: high 10067%, moderate 6633%,
and low 320% (24)

The multivariate distance dkl between two

sample vectors, k and l, is determined by computing
differences in each of the m variables. M is the
order of the distance, and here represents the
Euclidean distance (M = 2). The distance values
were transformed into a similarity matrix whose
elements are the similarity indices (similaritykl = 1dkl/dmax, where dmax is the largest distance in the data
set). The similarity scale ranges from zero
(dissimilar samples or variables) to one (identical

(eq. 1)

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samples or variables), and the larger the similarity

index, the smaller the distance between any pair of
samples or variable (32,33). The findings are
expressed as a two-dimensional tree named
dendrogram.
PCA is a multivariate method whose
principal components contain most of variability
from the data set in a much lower dimensional
space. PC1 or factor 1 is defined along the direction
of maximum variance of the whole data set,
whereas PC2 or factor 2 is on the direction that
describes the maximum variance of the subspace
orthogonal to PC1. The subsequent components are
taken orthogonally to those previously chosen, and
describe the maximum of the remaining variance.
Once redundant information is removed, only the
first few PCs are necessary to describe most of the
information contained in the original data set. The
data matrix X (I J), corresponding to I molecules
and J descriptors, is broken down into two matrices,
T and L, in such a way that X=TLT. The T matrix,
known as the score matrix, represents the position
(classification) of the compounds on the new
coordinate system where the PCs are the new axes.
Scores are integral to exploratory analysis because
they show intersample relationships. L is the
loadings matrix whose columns describe how the
new axes (PCs) are built from the old axes. It also
gives insight into the variables importance, that is to
say, which variables contribute more or less to each
PC or factor (32,33).
The Pirouette 3.11 software (34) displays
many entities that can help to explore the
relationships between samples, find samples
outliers, choose the optimal number of factors and
make decisions about variables to be excluded. The
outliers diagnosis was performed through the
Mahalanobis distance (Equation 2) (34, 35), which
is a distance computed from its k factor (PC) score.

RESULTS
Herein, thirteen prodrugs and corresponding
precursors were selected, and their percent values of
human intestinal absorption (% HIA) as well as the
score of absorption profile are listed in Table 1.
Percent human intestinal absorption refers to the
percentage of orally administered drug that reaches
the hepatic portal vein, and it has been used to infer
about drug bioavailability.
Among prodrugs that have exhibited higher
absorption levels are famciclovir, oseltamivir,
enalapril, quinapril and bacampicillin. Valacyclovir,
tenofovir diisoproxilate, benazepril, ramipril,
fosinopril, cefuroxime axetil, cefpodoxime proxetil,
and cefetamet pivoxil had moderate absorption
uptake. As expected, none of the selected prodrugs
presented low absorption profile.
Besides the properties considered in Ro5 and
Vebers expanded version to predict oral
bioavailability,
other
molecular
properties
[topological (Platt, Randic, Balaban, Harary,
Szeged, Wiener, Wiener polarizability indices),
geometric (ASA, ASA+, ASA-, ASA_H, ASA_P),
steric/hydrophobic (MR, molar refractivity),
electronic
(polarizability,
),
and
steric
(MSA_vdW)] were calculated, herein, in order to
explore differences between prodrugs and its
precursors as well as to identify which molecular
descriptors influenced more that discrimination.
Then, an exploratory data analysis was carried out
for the set of molecules selected. The findings are
shown in Figure 1 and 2.
According to the factors selection, the first
two PCs were responsible for explaining 83.79 % of
the total variance from the original data (Figure
1A). Regarding the scores plot for PC1 and PC2,
the first component was responsible for
discriminating prodrugs (right side; positive) from
drugs (left side; negative). The therapeutic class
seemed to be more considered in PC2. The loadings
table (Figure 1C) provides information on which
calculated properties had greater influence on
compounds discrimination. In PC1, intrinsic (MW;
0.42), steric/hydrophobic (MR; 0.43), electronic (;
0.42) and topological (rot_bonds; 0.42) descriptors
presented high loading values. In PC2, however,
topological (HBA_count; 0.68) and geometric
(PSA; 0.67) descriptors influenced more
compounds discrimination.
In addition, the plot of sample residual versus

(eq. 2)
In Equation 2, S is the score covariance
matrix and t is the mean score vector. Assuming
that the Mahalanobis distance is normally
distributed, a critical value (MDcrit) can be
determined from the chi squared distribution with k
degrees of freedom. If the samples Mahalanobis
distance exceeds MDcrit, that sample might be an
outlier.

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Mahalanobis distances (34) (Figure 2A) suggested

that there were no outliers. The sample residual
threshold (light green line in Figure 2A) considers a
95% confidence level interval, which is set
internally in Pirouette 3.11 (34). The compounds
did not exceed a threshold value, considering both
axes, which means that the calculated properties
were sufficient to describe the structural features of
the entire data set.
Furthermore, complementary findings were
obtained for both methods, HCA and PCA,
reinforcing the separation pattern, as can be seen in
the samples dendrogram (Figure 2B). The
compounds were grouped according to the pattern

observed in PC2, mostly like therapeutic classes.

Considering the similarity cursor at 0.5, or 50 %
similarity (dashed line) in the dendrogram of
samples, four sub-clusters were formed sharing 62
%
(TN_PRO;
CEFT_PRO,
CEFP_PRO,
CEFOX_PRO), 73 % (TN, PEN; OSEL, ACY), 60
% (QUI, BN; RAM; ENA; AMP; VAL_PRO; CEFT,
CEFP; CEFOX), and 59 % (QUI_PRO, BN_PRO;
RAM_PRO;
AMP_PRO;
FOS,
ANA_PRO;
OSEL_PRO, FAM_PRO) similarity, respectively.
FOS_PRO was isolated from the rest as also
observed in PCA findings (scores plot) where it
was placed at the bottom right side.

Figure 1. Findings found for exploratory data analysis. PCA findings: (A) factor selection, factor 1 and 2 discriminated 83.79% of
total variance from original data; (B) scores plot for PC1 (factor 1; 60.32 %) and PC2 (factor 2; 23.47 %), PC1 was responsible
for the separation between prodrugs (white losangle; right side) and drugs (black solid losangle; left side). Three molecules were
not properly separated, and are indicated by blue light arrows. (C) Loadings values for factor 1 and 2 (83.79 % cumulative);
numbers in red indicated the calculated descriptors which had more influence on compounds discrimination.

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Figure 2. Results obtained from exploratory data analysis (continuation from Figure 1). PCA findings: (A) Outliers
diagnosis through sample residual versus Mahalanobis distance. The sample residual threshold (green line) is based upon
95% probability limit (set internally in Pirouette program). HCA findings: (B) Dendrogram of samples. Similarity values
(%) are indicated inside the plot. Dashed line corresponds to the similarity cursor, which is placed at 0.5 index value.
Considering that, four sub-clusters can be found and FOS_PRO would be isolated from the rest.

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interestingly PC2 considered the therapeutic class.

At the scores plot (Figure 1B) it is possible to verify
that antibiotics are mostly placed at the upper side,
antivirals at the center/left side, and antihypertensive are at the center/bottom region of plot.
Ampicillin and bacampicillin were more distant
from the antibiotics group probably because
structural differences among penicillins and
cephalosporins.
In PC1, intrinsic, steric/hydrophobic,
electronic and topological molecular properties
were important for compounds discrimination. On
the other hand, at PC2, topological and geometric
descriptors presented higher influence. Steric,
geometric, and topological parameters are related to
the molecular shape and, then, play important role
in absorption and molecular recognition of drugs.
Molecular weight (MW) corresponds to
molecular mass of a chemical entity, and depends
on the chemical elements in the structure
(24,37,38). Considering the classical concept of
prodrug design, where a drug and some chemical
moiety are covalently attached, it would be
expected that prodrugs present higher MW values
than the corresponding parent drugs. MW was
indeed one of the molecular properties that most
influenced the discrimination process in PC1 (see
Figure 1C).
Drug-membrane or drug-receptor interactions
are associated with conformational arrangements
that, in turn, depend on the presence of rotatable
connections (rot_bonds) in a molecular system or
compound. Veber et al. (16) proposed that oral
bioavailability is dependent on molecular
flexibility, which could be inferred through the
number of rotatable bonds (rot_bonds values).
However, the introduction of atoms and sigma
bonds in molecules in order to increase rotatable
bonds can also become a problem, since the
excessive increasing of freedom degrees might
generate a molecule with a suboptimal
improvement on % HIA. That means, when the gain
in number of rotatable bonds is substantial, other
problems would affect the pharmacokinetic profile.
The prodrugs investigated in this study present
approximately ten rotatable bonds whereas the
corresponding drugs have around six rotatable
bonds. Thus, both have the number of rotatable
bonds less or equal to ten, which could provide
suitable bioavailability according to Verbers
proposition.

DISCUSSION
Nowadays, there are many drugs that do not possess
an optimal pharmacokinetic profile or impairing
therapeutic efficacy. One strategy adopted, in this
regard, is latentiation in order to generate prodrugs,
which would overcome biological barriers, and
finally, reach the receptor/target.
Regarding Table 1, the selected prodrugs
have presented higher % HIA values than their
parent drugs, and the score of absorption profile
changed from low to moderate, low to high, and
moderate to high (24). According to the
Biopharmaceutics Classification Scheme (BCS)
(24), drug substances are classified as follows:
Class I, high permeability and high solubility; Class
II, high permeability and low solubility; Class III,
low permeability and high solubility; Class IV, low
permeability and low solubility. In general, the
absorption of class II is over predicted by
absorption models because dissolution is the ratelimiting step of absorption. So, molecular features
as solubility, permeability, and diffusion rates (36)
can affect absorption and, consequently,
bioavailability.
Solubility
and
permeability
through
membranes are related to aspects such as molecule
size and lipid solubility, and can be numerically
expressed by some molecular descriptors, such as
molecular weight (MW), calculated n-octanol/water
partition coefficient (ClogP), and number of
rotatable bonds (rot_bonds). Drugs diffusion rate is
governed by the number of hydrogen bonds
provided by hydrogen bond acceptors (HBA) and
donors (HBD) groups. Therefore, physicochemical
descriptors as molecular polar surface area (PSA),
HBD and HBA can be applied to predict passive
diffusion, for instance. Thus, the introduction of
carrier groups in order to obtain a novel prodrug
would modify drugs molecular properties and,
consequently, solubility and permeability, which in
most of cases should be changed.
In general, prodrugs have presented higher
%HIA values than their parent drug. The
transformation
of
penciclovir,
oseltamivir
carboxylate, benazeprilate, ramiprilate, and
cefuroxime to their respective prodrugs caused a
remarkable increase in absorption, emphasizing the
importance of prodrug designing (latentiation).
Regarding PCA findings, the first component
discriminated prodrugs from drugs, and,
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Interestingly, two other molecular descriptors

neither included in Ro5 nor Vebers extended
version have presented high loading values in PC1
regarding the separation between drugs and
prodrugs, molar refractivity (MR) and polarizability
(). They are related to steric/hydrophobic and
electronic features, respectively. Thus, molecular
properties as MR and , not included in the rules of
Lipinski and Veber, should be also investigated for
designing novel prodrugs.
Complementary findings were observed at the
PCA and HCA analysis. According to the
dendrogram obtained, four groups were formed
where therapeutic class was mainly considered. The
first sub-cluster is contained of antibiotic prodrugs
(cephalosporin type), except to TN_PRO. The
second sub-group comprises antiviral drugs. A
mixture can be observed in the third sub-cluster
which are the anti-hypertensive (81 % similarity)
and cephalosporin drugs (81 % similarity). The
fourth sub-cluster comprises mostly antihypertensive (92 % similarity) and antiviral (66 %)
prodrugs. Both AMP and AMP_PRO are not part of
the antibiotic subgroups probably due to structural
differences among penicillin and cephalosporin
classes, corroborating the PCA findings.

relevant for the prodrug designing field.

ACKNOWLEDGMENTS
This work was supported by grants of the Provosts
Office for Research of University of So Paulo,
CAPES and CNPq (Brazil). The authors are grateful
to FAPESP (proc. nr.: 2013/18160-4).
CONFLICT OF INTEREST
The authors declare that they have no conflict of
interest.
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Thus, the findings are in agreement with the
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