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IJBPAS, May, 2017, 6(5): 941-952
ISSN: 2277–4998
941
IJBPAS, May, 2017, 6(5)
ANALYSIS OF THE LIGAND EFFICIENCY OF 4-THIAZOLIDINONE
DERIVATIVES WITH ANTITUMOR ACTIVITY
PATRICIA SANTOS BARBOSA AND JOSE GILDO DE LIMA*
Department of Pharmaceutical Sciences, Health Sciences Center, Federal University of
Pernambuco. Rua Prof. Arthur de Sá, S∕N, Cidade Universitária, Postal Code: 50740-
521, Recife – PE, Brazil
*Corresponding author: E Mail: jgildolima@gmail.com; Tel.: +55-081-21268511-;
fax: +55-081-21268510;
ABSTRACT
Ligand efficiency analysis has been shown to be useful in the selection and optimization
of new bioactive compounds. In order to direct the planning for new 4-thiazolidinones
as regards in vitro antitumor activity, ligand efficiency (LE) calculations, fit quality
(FQ) and ligand lipophilic efficiency (LipE) were conducted for 121 4-thiazolidinone
derivatives found in the literature. Average values for LE and LipE were found to be
below adequate minimum values. 14% of compounds studied showed an LE ≥ 0.3 and
only one compound had a LipE ≥ 5 -7. 29% of the compounds had FQ values above 0.8
and three compounds with values above 1 showed exceptional LE.
Keywords: Ligand efficiency; Ligand lipophilic efficiency; 4-Thiazolidinones;
Cytotoxicity; Anticancer
INTRODUCTION
Cancer is commonly defined as a group
composed of more than 100 diseases
characterized by uncontrolled growth of
abnormal cells in the body which is the
leading cause of deaths in the world [1].
In 2012, 14 million new cases and 8.2
million deaths caused by cancer took
place. More than 70% of the deaths
occurred in Africa, Asia and South and
Central America [2]. Advanced therapies
have been used in the treatment of
cancer patients but cells have quickly
acquired multidrug resistance (MDR)
[3]. The main MDR mechanism is
Received 22
nd
Nov. 2016; Revised 21
st
Dec. 2016; Accepted
1
st
March
2017; Available online 1
st
May
2017
Patricia Santos Barbosa and Jose Gildo De Lima Research Article
942
IJBPAS, May, 2017, 6(5)
overexpression of the P-glycoprotein
(Pgp), a carrier protein that acts as an
anti-carcinogenic drug efflux pump [4].
4-thiazolidinones (Figure 1) have
continued to be of interest to the
pharmaceutical industry due to their
hypoglycemic, anti-inflammatory,
anticonvulsant, antidiabetic, antitumor,
antiviral and cardiovascular
pharmacological activities, among others
[5]. Several compounds containing the
4-thiazolidine nucleus with substitutes at
positions 2, 3 and 5 have demonstrated
good cytotoxicity against cancer cell
lines including cells with Pgp
overexpression [6-9]. Ligand efficiency
metrics quantify molecular properties
needed to ensure compound affinity by
the therapeutic target. Ligand efficiency
calculations have been applied with
success in fragment selection and
optimization, bioactive molecules and
lead compounds [10]. The concepts of
ligand efficiency (LE), binding free
energy by heavy atoms and ligand
lipophilic efficiency (LipE) which
combines potency and lipophilicity are
the most used in the discovery of drugs
[11-14].
S
N
R
2
R
1
O
R
3
1
2
3 4
5
Figure 1: 4-Thiazolidinone nucleus
In LE calculation, NHAs are handled
without distinction even if the sizes and
binding properties are different. In
anticipation of this inconvenience, the fit
quality (FQ) proposes a correction of LE
values making this metric independent of
the influence of differences in the size of
atoms [9, 10]. There are already several
published studies using ligand efficiency
analysis as an aid in the planning of new
drugs [15-19].
Based on the need to direct the planning
of new 4-thiazolidinones for better
cytotoxicity against cancerous cells, the
present study had as its objective the
analysis of LE, FQ and LipE of
molecules with proven activity
containing the 4-thiazolidinone nucleus
in their chemical structure.
MATERIALS AND METHODS
To carry out the research, a database of
4-thiazolidinone compounds from the
literature was generated [20-34]. Only
articles that presented the IC50 of 4-
thiazolidinone derivatives for cytotoxic
activity in vitro were incorporated into
the database. Some compounds showed
the (IC50) average inhibitory
concentration in weight/volume units. In
these cases, it was necessary to perform
the IC50 conversion to molarity units.
LogP values were calculated using a
ChemAxon computer program (online
Patricia Santos Barbosa and Jose Gildo De Lima Research Article
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IJBPAS, May, 2017, 6(5)
version 5.4 chemicalize.org).
Compounds with negative cLogP were
not included in the database. For the
calculation of ligand efficiency (LE)
[35], Fit Quality (FQ) [9] and ligand
lipophilic efficiency (LipE) [10] the
following formulas were used:
Equation 1: LE = 1,4xpIC50/NHA
Equation 2:
FQ=
L
E
0
.
0
7
1
5
+
(
7
.
5
3
2
8
x
N
H
A
-1
)
+
(
2
5
.
7
0
7
9
x
N
H
A
-2
)
-
(
3
6
1
.
4
7
2
2
x
N
H
A
-3
)
Equation 3: LipE = pIC50-cLogP
Where NHA is the number of different hydrogen
atoms; pIC50 = -LogIC50; cLogP is the calculated
partition coefficient. The database was created and
analyzed using Microsoft Excel® software. The
charts were generated using OriginPro 8 SR2 v
8.0891 (B891) software.
RESULTS AND DISCUSSION
A ligand efficiency analysis of 121 4-
thiazolidinone compounds with
cytotoxic activity was calculated. Table
1 shows the average values found for the
compounds studied. The average value
calculated for LE was 0.26, lower than
the 0.3 LE acceptable minimum.10
When FQ was applied for correction of
the LE average value, the new average
value found was 0.75.
The average cLogP found was 4.51
which obeyed the Rule of Five proposed
by Lipinski.36 However, the average
pIC50 (5.42) was not very different from
the average cLogP and so the LipE
average (0.91) was well below ≥ 5-7, an
ideal value for this metric [10]. In
addition, Schultes et al. showed that
successful compounds have, on average,
pIC50 equal to 8 [37]. The histogram
(Figure 2) shows the number of
compounds based on the values
calculated for LE. Only 14% of the
compounds have LE values ≥ 0.3, i.e.,
they have greater chances in succeeding
[38]. The vast majority of compounds
had LE calculated values below the ideal
due to NHA. It is known that NHA can
influence lipophilia and is considered a
risk factor in the planning for drugs. The
majority of compounds with high
lipophilia has inadequate
pharmacokinetics and toxicology. On the
other hand, the affinity for the compound
target also increases based on lipophilia
[39, 40].
In order to verify the influence of NHA
on LE values, six 4-thiazolidinone
derivatives present in the database were
selected and their LE, pIC50 and NHA
values were compared (Table 2).
Compounds 1 [20], 2 [20] and 3 [31]
have pIC50 equal to 0.9 µM, however,
only compound 3 has an acceptable LE.
This is due to NHA. In compound 3, it
took 27 NHA to produce a pIC50 equal to
compounds 1 and 2 which needed 34 and
33 NHA, respectively. Compounds 4
[31], 5 [24] and 6 [27] fit the same
profile. Both have a pIC50 of 9 µM and
only compound 4 has an acceptable LE,
i.e., compound 4, with 0.37 Kcal•mol-1
Patricia Santos Barbosa and Jose Gildo De Lima Research Article
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IJBPAS, May, 2017, 6(5)
per NHA, requires 19 different atoms of
hydrogen to produce an pIC50 equal to
compounds 5 and 6. On the other hand,
the latter require more heavy atoms to
produce pIC50 equal to compound 4.
FQ values near 1.0 indicate a wonderful
molecule binding affinity for the
therapeutic target. So, removing the
influence of the difference in molecular
size, we have 29% of the compounds
with an FQ > 0.8 (Figure 3). Still,
compounds with FQ values > 1 have an
exceptional affinity for the molecular
target [10]. In Figure 3 three FQ
compounds above 1 are marked.
According to Lipinski, LogP values for
compounds with good oral
bioavailability must be equal or less than
5. Figure 4 shows charts for cLogP x
pIC50 (Figure 4a) and NHA x pIC50
(Figure 4b). A total of 37% of the
compounds studied have cLogP values
greater than 5, i.e., they disobey one of
the Lipinski rules for drugs with good
oral bioavailability [36]. Analyzing
Figure 4a, we did not notice a tendency
to increase pIC50 in the cLogP function.
This demonstrates that the pIC50 for
cytotoxicity of 4-thiazolidinones is not
dependent on a lipophilia increase and
that it is possible to synthesize new
chemical entities according to Lipinski's
LogP value rule with excellent cytotoxic
activity against cancer cells. We also
came to the same conclusion when we
observed the NHA x pIC50 chart (Figure
4b). We realized that most of the
compounds that have NHA between 25
and 35, however, do not have a tendency
to increase the pIC50 based on NHA.
In Figure 4a, two compounds
synthesized by Wang et al. [20] are
marked. These compounds (Figure 5)
are examples of bioactive molecules
with LogP within Lipinski's standards36
with pIC50 exceeding 8 [37]. In addition,
they have values for LE ≥ 0.3 and FQ >
1 which fit into the select group of
molecules that possess an exceptional
affinity for the therapeutic target.
The LE x LipE chart (Figure 6) allows
us to analyze LE and LipE together.
With cLogP greater than pIC50, 31% of
the compounds had LipE values less
than zero. This means that these
molecules have a greater affinity for n-
octanol than for the molecular target
[10]. Two lines divide the compounds
with minimal favorable LE and LipE
values.
From 121 compounds studied we
observed only one that stood out for LE
and LipE values (Figure 6). This
compound (Figure 7) was synthesized
by Feitoza et al. [21]. It has a better
Patricia Santos Barbosa and Jose Gildo De Lima Research Article
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IJBPAS, May, 2017, 6(5)
chance of being successful than the other
compounds under study.
The LE metric penalizes compounds
with the same potency and different
NHA, whereas heavier compounds have
worse physicochemical and ADME
properties. Yet the LipE metric penalizes
compounds that have increased potency
based on increased lipophilia. High
LogP values are associated with low
solubility, absorption and metabolic
stability in addition to an increased risk
of non-specific interactions and toxicity
[40].
Table 1: Average values calculated for ligand efficiency (LE), fit quality (FQ) and lipophilic efficiency (LipE)
for 121 compounds studied containing a 4-thiazolidinone nucleus.
Quantity of
compounds pIC50 NHA LE FQ cLogP LipE
121 5.42
± 0.62
30.12
± 4.33
0.26
± 0.05
0.75
± 0.08
4.51
±1.44
0.91
± 1.59
Figure 2: Distribution of ligand efficiency values for 121 4-thiazolidinone derivatives
Table 2: Values for the ligand efficiency (LE), minimum inhibitory concentration (pIC50) and the number of
different hydrogen atoms (NHA) for 6 selected 4-thiazolidinone derivatives
Compound LE (Kcal•mol
-
1
per NHA) IC
50
(µM) NHA
1 0.24 0.9 34
2 0.26 0.9 33
3 0.31 0.9 27
4 0.37 9 19
5 0.27 9 26
6 0.17 9 41
Figure 3: Fit quality values (FQ) x the number of different hydrogen atoms (NHA) for 121 4-thiazolidinone
derivatives
Patricia Santos Barbosa and Jose Gildo De Lima Research Article
946
IJBPAS, May, 2017, 6(5)
Figure 4: cLogP values x pIC50 (3a) and the number of different hydrogen atoms (NHA) x pIC50 (3b) for 121 4-
thiazolidinone derivatives.
NS
N
O
O
O
O
R
(7) R= 5F (8) R= 6F
IC
50
25nM IC
50
28nM
pIC
50
7.60 pIC
50
7.55
cLoP 4.36 cLogP 3.75
LE 0.30 LE 0.31
FQ 1.02 FQ 1.02
LipE 3.19 LipE 3.85
Figure 5: Synthesized compounds by Wang et al.20 with cLogP within Lipinski's standards
Figure 6: Ligand efficiency (LE) x ligant lipophilic efficiency (LipE) for 121 4-thiazolidinone derivatives
N
NN
S
N
CH
3
O
p
I
C
50
5
.
7
4
cLogP 0.48
LE 0.50
FQ 0.73
LipE 5.26
Figure 7: Chemical structure and data of compound synthesized by Feitoza et al..34
CONCLUSION
The ligand efficiency analysis and
lipophilic efficiency of 121 4-
thiazolidinone cytotoxic compounds
under study showed that 14% of them
have LE ≥ 0.3, 29% have an FQ above
0.8. Only one compound has a LipE ≥ 5-
7, this is due to a disproportion between
the pIC50 and the cLogP, or i.e., in
general, the compounds studied have
high lipophilia in relation to potency.
However, the data showed that the
increase in potency is independent of
lipophilia and the NHA. Even being
aware of the Rule of Five there were
37% of the compounds which had a
cLogP exceeding five. Consequently, we
must stress the necessity for adequate
Patricia Santos Barbosa and Jose Gildo De Lima Research Article
947
IJBPAS, May, 2017, 6(5)
use of an efficiency analysis of the
ligand during the planning of new 4-
thiazolidinone antitumor analogs.
ACKNOWLEDGEMENTS
"This work was supported by Conselho
Nacional de Desenvolvimento Científico
e Tecnológico (CNPq-Brazil). We thank
CAPES for the student fellowships. We
also thank the ChemAxon software
company for on-line computer program".
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