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Journal of Biosciences and Medicines, 2020, 8, 42-53
https://www.scirp.org/journal/jbm
ISSN Online: 2327-509X
ISSN Print: 2327-5081
Molecular Docking and Evaluation of
Antileishmania Activity of a Ruthenium
Complex with Epiisopiloturine and Nitric Oxide
Joabe Lima Araújo1,2,3*, Ruan Sousa Bastos2,3,4, Gardênia Taveira Santos5,
Michel Muálem de Moraes Alves6, Kayo Alves Figueiredo7, Lucas Aires de Sousa8,
Ionara Nayana Gomes Passos2, Fernando Aécio de Amorim Carvalho9,
Francisco das Chagas Alves Lima10, Jefferson Almeida Rocha2,3
1Postgraduate Program in Nanoscience and Nanobiotechnology, Department of Genetics and Morphology, University of Brasília,
Brasília, DF, Brazil
2Research Group in Natural Sciences and Biotechnology, Department of Natural Sciences/Chemistry, Federal University of
Maranhão, Grajaú, MA, Brazil
3Research Group in Medicinal Chemistry and Biotechnology, QUIMEBIO, Federal University of Maranhão, São Bernardo,
MA, Brazil
4Postgraduate Program in Medicinal Chemistry and Molecular Modeling, Federal University of Pará, Belém, PA, Brazil
5Department of Nursing, State University of Maranhão, Colinas, MA, Brazil
6Department of Veterinary Morphophysiology, Federal University of Piauí, Teresina, PI, Brazil
7Department of Health, Federal Institute of Education, Science and Technology of Piauí, Teresina, PI, Brazil
8Postgraduate Program in Materials Science, Center for Social Sciences, Health and Technology, Federal University of Maranhão,
Imperatriz, MA, Brazil
9Department of Biochemistry and Pharmacology, Federal University of Piauí, Teresina, PI, Brazil
10Department of Chemistry, Quantum Computational Chemistry Laboratory, Federal University of Piauí, Teresina, PI, Brazil
Abstract
Leishmaniasis is an infectious disease that affects both animals and humans,
caused by flagellated parasites belonging to the genus
Leishmania
. The disease
is estimated to reach about 700,000 to 1 million people, causing the deaths of
20 to 30,000 individuals annually. Thus, the present study aims to perform mo-
lecular docking tests and evaluation of antileishmania activity
in vitro
of a ru-
thenium complex with epiisopiloturine and nitric oxide.
AutoDockTools-
1.5.6
software
was used to perform molecular docking tests. Molecular targets were
considered rigid, and Epiruno2 considered flexible. The genetic algorithm La-
marckian (AGL) with global search and pseudo-
Solis and Wets with local
search were the methods adopted in the docking. The most promising results
of molecular interaction were achieved in the targets Pteridine reductase and
UDP-glucose Pyrophosphorylase with rates of −10.68 Kcal∙mol−1 and −
10.51
Kcal∙mol−1, respectively. This demonstrates that Epiruno2 has molecular affinit
y
with the targets of
L
.
major
.
In vitro
assays prove the antileishmania activity of
How to cite this paper:
Araújo, J.L., Bastos
,
R
.S., Santos, G.T., de Moraes Alves, M.M.,
Figueiredo, K
.A., de Sousa, L.A.,
Passos,
I
.N.G., de Amorim Carvalho, F.A.,
das
Chagas Alves Lima,
F. and Rocha, J.A.
(20
20) Molecula
r Docking and Evaluation
of Antileishmania Activity of a Ruthenium
Complex with Epiisopil
o
turine and Nitric
Oxide
.
Journal of Biosciences and Medicines
,
8
, 42-53.
https://doi.org/10.4236/jbm.2020.85005
Received:
March 7, 2020
Accepted:
April 27, 2020
Published:
April 30, 2020
DOI: 10.4236/jbm.2020.85005 Apr. 30, 2020 42 Journal of Biosciences and Medicines
J. L. Araújo et al.
1. Introduction
Leishmaniasis is a disease that affects more than 98 countries worldwide, with
about 700,000 to 1 million new cases reported annually, and an annual rate of 20
to 30,000 deaths [1]. There are several ways for the disease to manifest clinically,
and may present as cutaneous, mucocutaneous and visceral. Infection with
Leish-
mania major
(
L
.
major
) species has a chronic evolution that affects the structures
of the nasopharyngeal epidermis and cartilage, either localized or diffuse [2]. The
parasitic cycle results from the abundance of carbohydrates on the surface of
Leishmania
, which includes lipophosphoglycans, glycosylphosphatidylinositol
lipid-anchored proteins and proteophosphoglycans [3]. These glycoproteins are
part of the promastigote infectious glycocalyx, which is the most important
process in host infectivity [4] and phlebotomine interaction [5].
After diagnosis, the patient undergoes treatment that depending on the in-
fecting strain will be treated with some of the drugs available on the pharma-
ceutical market, they are: pentavalent antimonial; AmBisomew; liposomal; am-
photericin B; miltefosine and diamidines, among others. All of these drugs are
potentially toxic and have reduced efficacy in addition to adverse side effects.
That in many cases, the patient chooses not to undergo treatment so that he does
not suffer from side effects caused by drugs [6] [7].
Besides this problem, the pharmaceutical industries neglect investments in the
search for new pharmacological agents that present high inhibition rates with
new mechanisms of action and low toxicity. This lack of interest is related to mar-
ket demand, as it is a neglected disease, that is, it affects only underdeveloped
and developing countries, the sector has high risks of not making profits on their
investments, because the population would not be able to afford it. With the
costs of treatment, even the state would not be able to finance the services of-
fered by the industries [8].
Thus, there is a clear need to search for new compounds with pharmacological
potential and low toxicity by alternative methods that bring reliability in their
results, speed and cost benefit. Thus, computational quantum chemistry presents
itself as a promising alternative, using several computational tools that predict
molecular properties related to a pharmacological potential. Using the laws of
quantum chemistry and various programming techniques that are capable of
predicting energy state, molecular structures, vibrational frequencies of atomic
and molecular systems and molecular interaction between two molecules de-
vel-oping virtual models saving time and materials that would be wasted on ex-
periments in the field laboratory [9] [10].
the complex in the face of promastigote forms with inhibition of growth, con-
cluding through this study that the Epiruno2 complex has antileishmania activity.
Keywords
Molecular Docking Simulation, Neglected Diseases,
Leishmania major
Copyright © 2020 by author(s) and
Scientific
Research Publishing Inc.
This work is licensed under the Creative
Commons Attribution International
License (CC BY
4.0).
http://creativecommons.org/licenses/by/4.0/
Open Access
DOI: 10.4236/jbm.2020.85005 43 Journal of Biosciences and Medicines
J. L. Araújo et al.
In this sense, ruthenium (Ru) complexes have become attractive in pharma-
cological studies because they have low toxicity and are an excellent conductor
of energy when dealing with a transition metal, where it plays an important role
in the bioactive process of a compound in reaction with a target disease, having
little energy loss in its path [11] [12]. The Ru complex with epiisopiloturin and
nitric oxide (Epiruno2) was synthesized by Rocha (2018) in anti-schistosoma
mansoni studies, where the Epiruno2 complex showed schistosomicidal activity
in sílico
and
ex vivo
studies. There was a 10-fold increase in the biological activ-
ity of Epiisopiloturin (EPI) when coupled with the Ru complex against Schisto-
soma parasites, eliminating 60% of male worms at a concentration of 50 µM
within 72 hours, showing antiparasitic activity [13].
Associated with the antiparasitic schistosomicidal effect presented by the Epi-
runo2 complex in studies by Rocha (2018), we assume that the complex has anti-
leishmania activity. Thus, the present study aims to perform molecular docking
tests and evaluation of antileishmania activity
in vitro
of a ruthenium complex
with epiisopiloturine and nitric oxide.
2. Materials and Methods
2.1. Molecular Docking
The 3D molecules of
L
.
major
targets were extracted from the PDB (
Protein data
Bank
) database with codes 5g20 (Glycyl Peptide N-tetradecanoyltransferase); 5nzg
(UDP-glucose Pyrophosphorylase); 5c7p (Nucleoside diphosphate kinase); 1e7w
(Pteridine reductase); and 1ezr (
Nucleoside hydrolase
) [14] prepared for dock-
ing by removing mutant chains and all water molecules, ions and other groups
using
Chimera v
.13.1
software
[15] [16].
The three-dimensional molecular structure of the Epiruno2 complex was de-
signed using
GaussView
5.0
software
[17] and optimized by DFT (Density Func-
tional Theory) calculation using the B3lyp functional and the 6-311++G (d, p)
available in
Gaussian
09
W software
[18] [19].
The molecular docking process followed the protocol developed by Rocha and
collaborators, with some modifications [20]. All molecular docking procedures
were performed by
AutoDockTools-
1.5.6
software
[21].
L
.
major
targets and the
Epiruno2 complex were prepared for docking simulations, where targets were
considered rigid and Epiruno2 was considered flexible. Partial charges were cal-
culated after the addition of all hydrogens. The nonpolar hydrogen atoms of the
protein and binder were subsequently fused. A 60 × 60 × 60 point cubic box with
a spacing of 0.375 Å between grid points was generated for the simulations. The
molecular affinity grid centers were defined from the coordi-nates of the atoms
of their respective active sites Asn376, Lys380, Gly91, Asn109 and Asp15, re-
spectively.
The Lamarckian global search (LGA) genetic algorithm [22] and the pseu-
do-Solis and Wets [23] local search (LS) methods were applied in the search for
molecular docking. The Epiruno2 complex was subjected to 100 independent
DOI: 10.4236/jbm.2020.85005 44 Journal of Biosciences and Medicines
J. L. Araújo et al.
runs of molecular coupling simulations [24]. The remaining parameters were set
to default values.
Molecular docking analysis focused on the results that presented lower fitting
conformation with lower
a
bind
G
energy, in addition to the interactions by hy-
drogen bridge and inhibition constant presented by the Epiruno2 complex in the
of the molecular targets of
L
.
major
.
2.2. In Vitro Trials on Promastigote forms MHOM/IL/80/Friedlin
of L. major
For
in vitro
assays, the method adopted by Carneiro and collaborators was used,
with some modifications [25]. The MHOM/IL/80/Friedlin promastigotes of
L
.
major
were donated by the Laboratory of Antileishmania Activity, located at the
Research Core in Medicinal Plants of the Federal University of Piauí—UFPI and
cultivated in Schneider media (Sigma, USA), supplemented with 10% bovine fetal
serum (BFS) (Sigma, USA) and penicillin-streptomycin 10,000 IU/10mg (Sigma,
USA) at 26˚C in a greenhouse of biological oxygen demand (BOD).
L
.
major
promastigote forms MHOM/IL/80/Friedlin in log phase were seeded
1 × 106 parasites per well in a 96-well cell culture microplate containing supple-
mented Schneider medium and Epiruno2 at serial concentrations of 800 to 6.25
µg/mL, respectively. Then the plates were incubated in a BOD greenhouse at
26˚C. After 48 h resazurine (1 mM) was added and the plate was re-infiltrated in
the BOD incubator for another 6 h. Then the spectrophotometer reading was
performed to obtain the optical density at 550 nm. Negative control was per-
formed with Schneider medium at 0.2% DMSO and considered as 100% viability
of the parasites. The amphotericin B (Amp-B) at a concentration of 2 µg/mL was
used as a positive control to validate the experiment.
3. Results and Discussion
3.1. Molecular Docking
The evaluation criteria were defined by the results that showed lower cluster
conformation with lower
a
bind
G
energy, besides the hydrogen bridge interac-
tions and inhibition constant presented by the Epiruno2 complex against the
L
.
major
molecular targets.
The molecular docking between the Epiruno2 complex and the 1e7w protein
obtained the lowest
a
bind
G
energy among all molecular couplings performed in
this study, obtaining an energy of −10.68 Kcal∙mol−1 and an inhibition constant
of 14.8 nM (Table 1). This low
a
bind
G
energy indicates high molecular affinity of
the complex with the target protein [26]. Thus, inhibiting its action would be to
interrupt the disease development process, since the 1e7w enzyme has a function
of reducing conjugated and unconjugated pterins, one example is biopterin and
dihydrobiopterin (DHB), followed by 5, 6, 7, 8-tetrahydrobiopterin (THB) or
DHF folate. It is the only protein known to reduce biopterin in Leishmania,
proving to be essential for
in vivo
growth through genetic knockout studies [27].
DOI: 10.4236/jbm.2020.85005 45 Journal of Biosciences and Medicines
J. L. Araújo et al.
Table 1. Molecular affinity parameters of the Epiruno2 complex with
L
.
major
targets.
Complex
(Protein-ligand)
a
bind
G∆
(kcal∙mol
−1
)
Kib (µM)
Number of independent
docking runs
Number of conformations
in the first ranked cluster
Amino acids that interact through
hydrogen bondsc
Epiruno2/1e7w −10.68 14.8 nM 100 7 Asp232, Lys198, Ser111, Ser227
Epiruno2/5nzg −10.51 19.74 nM 100 6 Asp221, Gly220, Lys95
Epiruno2/5g20 −9.65 83.81 nM 100 81 -
Epiruno2/5c7p −8.22 935.7 nM 100 43 Arg104, Asn114, Ser98
Epiruno2/1ezr −8.19 996.06 nM 100 4 Pro11, gln40
Note: Epiruno2—ruthenium complex with epiisopiloturine and nitric oxide; 1e7w—Pteridine reductase; 5nzg—UDP-glucose Pyrophosphorylase;
5g20—Glycyl Peptide N-tetradecanoyltransferase; 5c7p—Nucleoside diphosphate kinase; and 1ezr—Nucleoside hydrolase. (Araújo
et al
., 2020).
The most intense interactions between the target protein and the Epiruno2
complex occur between the residues Asp232, Lys198, Ser111 and Ser227, places
where the highest intermolecular forces act (Figure 1).
The Epiruno2 complex also showed excellent molecular affinity results with
the target protein 5nzg of
L
.
major
, obtaining a
a
bind
G
energy of −10.51 Kcal∙mol−1
(Table 1) and formation of three hydrogen bridges located on amino acids Asp211,
Gly220 and Lys95, where the most intense interactions between the complex and
the target protein occur (Figure 1). This may be related to UGP (UDP—glucose
pyrophosphorylase) catalyzing the synthesis of activated form glucose, UDP-Glc,
uridine triphosphate (UTP) and glu-cose-1-phosphate (Glc-1p). Because the
UDP-Glc reaction is critical in the production of carbohydrates such as cell surface
glycans and other pathogen processes becoming an attractive target in interac-
tion and molecular inhibition studies [28] [29] [30]. The resulting inhibition
constant was 19.74 nM, presenting antileishmania inhibitory activity of the Epi-
runo2 complex against target protein 5nzg (Table 1).
This result indicates that the Epiruno2 complex has antileishmania inhibitory
activity, since docking studies analyze the inhibitory action of coupled compounds
at the active site of the target protein [26] even if there is a difference between
in
sílico
and
in vitro
experiments, the results tend to differ, where
in sílico
studies
by molecular docking pre-dict quickly and reliably if a compound has biological
activity and experimental labora-tory studies validate their analyzes, complement-
ing each other, providing technical via-bility in the results presented [31] [32].
The 5g20 protein also showed molecular affinity with the Epiruno2 complex
obtaining attractive
a
bind
G
energy in docking molecular affinity studies with −9.65
Kcal∙mol−1 and an inhibition constant of 83.81 nM [26] (Table 1). This molecu-
lar interaction did not result in hydrogen bridges, unlike previous interactions
between the Epiruno2 complex with the 1e7w and 5nzg proteins that had 4 and 3
hydrogen bridges, respectively, however, the interactions in the Val374, Leu227
and His219 residues make intense interactions in the active site borders of the
protein, in particular the interactions Val374 with O1 and Leu227 with O2 and
DOI: 10.4236/jbm.2020.85005 46 Journal of Biosciences and Medicines
J. L. Araújo et al.
Figure 1. Molecular docking between Epiruno2 complex and 1e7w and 5nzg target proteins. (a) Docking
at target protein active site 1e7w; (b) molecular interaction between Epiruno2 and target protein
1e7w; (c) Docking at 5nzg target protein active site; (d) molecular interaction between Epiruno2 and
5nzg target protein.
both residues with C8 (Figure 2). These interactions at the edges of the active site
make the Epiruno2 complex have a very promising high inhibitory action, and the
tertiary structure is part of recognition elements that facilitate the molecular in-
teractions between protein and ligand, in this case the Epiruno2 complex [33] [34].
Molecular docking between the 5c7p protein and the Epiruno2 complex
formed three hydrogen bridges at amino acids Arg104, Asn114 and Ser98
(Figure 2) and showed
a
bind
G
energy of −8.22 Kcal∙mol−1 and an inhibition con-
stant of 935.7 nM (Table 1). These results are promising against this indispensa-
ble protein for the maintenance of intracellular nucleoside triphosphate (NTP)
levels [35]. They carry the γ-phosphoryl group from an NTP to a nucleoside di-
phosphate (NDP) through a functional scheme called ping-pong involving the
covalent intermediate phosphohistidine. Eukaryotic NDKs are composed of 15
to 18 KDA subunits with similarities in their general structures and a conserved
active site [36] [37].
DOI: 10.4236/jbm.2020.85005 47 Journal of Biosciences and Medicines
J. L. Araújo et al.
Figure 2. Molecular docking between the Epiruno2 complex and the 5g20, 5c7p and 1ezr proteins. (a) Docking at active site of protein
5g20; (b) molecular interaction between 5g20 protein and Epiruno2 complex; (c) molecular interaction between 5c7p protein and
Epiruno2 complex; (d) Docking at active site of protein 1ezr; (e) molecular interaction between 1ezr protein and Epiruno2 complex.
The 1ezr protein can be identified in free extracts of Leishmania cells, is also
present in several parasitic protozoa. It is a protein useful in parasitic infections,
acting as a catalyst for the hydrolysis of both purine and pyrimidine nucleosides
[38] [39], where its inhibition is fundamental for the treatment of
L
.
major
. In
this sense, the Epiruno2 complex presented interesting interaction and molecular
affinity results, obtaining a
a
bind
G
energy of −8.19 Kcal.mol−1 and an inhibition
constant of 996.06 nM [26] (Table 1). The most intense interactions between the
complex and the protein occur at residues Pro11 and Gln40, the two hydrogen
bonds formed (Figure 2).
3.2. In Vitro Trials on Promastigote Forms MHOM/IL/80/Friedlin
of L. major
In these trials we evaluated the leishmanicidal effects of the Epiruno2 complex
against
L
.
major
promastigote MHOM/IL/80/Friedlin parasites. The Epiruno2
complex showed 50.53% inhibition of promastigote growth at a concentration of
800 µg/mL (Figure 3), a significant reduction by analyzing the half maximal in-
hibitory concentration (CI-50) (Table 2) showing antileishmania activity, con-
firming the results presented
in sílico
tests by molecular docking. However, these
DOI: 10.4236/jbm.2020.85005 48 Journal of Biosciences and Medicines
J. L. Araújo et al.
values are not considered clinically relevant, according to Santos
et al
. [40],
which defines in their studies that only IC-50 lower than 500 µg/mL can be con-
sidered therapeutically relevant.
It is observed that the results presented in molecular docking analyzes were
more promising than the results presented
in vitro
assays. This may be related to
the topological polar surface area (TPSA), which uses functional groups obtained
from a structural database, avoiding calculations of the ligand’s three-dimensional
(3D) structures, in this case the Epiruno2 complex or the confirmation of which
conformation. Since this biological method is relevant, this method is used in 2D
structures for 14 sets of diverse pharmacological activity data. This methodology
is promising for classic 2D descriptors such as calculated LogP (ClogP) and cal-
culated molar refractivity (CMR) in the 2D-QSAR literature [41].
The discovery of new antileishmania chemical compounds has long been rea-
lized from the isolation of plant extracts. There are already several extracts and
compounds that have proven antileishmania activity on promastigote and amas-
tigote forms of through
in vitro
assays [42] [43] [44]. Despite several microbio-
logical studies, several analyzes of new compounds extracted from natural and
synthetic resources are still needed, as the search for new pharmacological po-
tential leishmanicide has been important, since the drugs in the pharmacological
market have high toxicity and reduced efficacy [6] [45].
Figure 3. IC-50 of the Epiruno2 complex against
L
.
major
promastigotes.
Table 2. IC-50 values of
L
.
major
promastigotes in the presence of the Epiruno2 complex.
Epiruno2 complex
L
.
major
MHOM/IL/80/Friedlin
IC-50
800 µg/mL
Note: IC-50 – half maximal inhibitory concentration (Araújo
et al
., 2020).
DOI: 10.4236/jbm.2020.85005 49 Journal of Biosciences and Medicines
J. L. Araújo et al.
4. Conclusions
The Epiruno2 complex presented antileishamania activity both
in sílico
studies
by molecular docking and
in vitro
study. Its best molecular affinity parameter
presented in docking studies was for target proteins 1e7w and 5nzg with
a
bind
G
energies −10.68 Kcal∙mol−1 and −10.51 Kcal∙mol−1, respectively. In addition to
these two targets, it was found that the complex has molecular affinity for the
other molecular targets of
L
.
major
analyzed in this study.
In vitro
assays proved the antileishmania activity of the complex against
L
.
major
promastigotes MHOM/IL/80/Friedlin with significant growth inhibitions.
However, the values are not considered clinically relevant, concluding from
in
sílico
and
in vitro
studies that the Epiruno2 complex has antiparasitic activity
that can be tested on other Leishmania targets such as
L
.
amazonensis
and
L
.
Chagasi
and also in other pathogens.
Acknowledgements
To the Department of Natural Sciences/Chemistry at the Federal University of
Maranhão—UFMA, campus of Grajaú, MA and to the members of the Labora-
tory of Antileishmania Activity, located at the Research Center for Medicinal
Plants at the Federal University of Piauí—UFPI.
Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this paper.
References
[1] Colina-vegas, L.,
et al
. (2019) Antiparasitic Activity and Ultrastructural Alterations
Provoked by Organoruthenium Complexes against
Leishmania amazonensis
.
New
Journal of Chemistry
, 43, 1431-1439. https://doi.org/10.1039/C8NJ04657C
[2] Scott, P. and Novais, F.O. (2016) Cutaneous Leishmaniasis: Immune Responses in
Protection and Pathogenesis.
Nature Reviews Immunology
, 16, 581-592.
https://doi.org/10.1038/nri.2016.72
[3] Ilg, T. (2000) Proteophosphoglycans of Leishmania Parasitol.
Today
, 16, 489-497.
https://doi.org/10.1016/S0169-4758(00)01791-9
[4] Descoteaux, A. and Turco, S.J. (1999) Glycoconjugates in Leishmania Infectivity.
Biochimica et Biophysica Acta
, 1455, 341-352.
https://doi.org/10.1016/S0925-4439(99)00065-4
[5] Sacks, D.L. (2001) Leishmania-Sand Fly Interactions Controlling Species-Specific
Vector Competence: Microreview.
Cellular Microbiology
, 3, 189-196.
https://doi.org/10.1046/j.1462-5822.2001.00115.x
[6] Croft, S.L. and Coombs, G.H. (2003) Leishmaniasis-Current Chemotherapy and
Recent Advances in the Search for Novel Drugs.
Trends in Parasitology
, 19, 502-508.
https://doi.org/10.1016/j.pt.2003.09.008
[7] Zuben, A.P.B.,
et al
. (2014) The First Canine Visceral Leishmaniasis Outbreak in
Campinas, State of São Paulo Southeastern Brazil.
Revista da Sociedade Brasileira de
Medicina Tropical
, 47, 385-388. https://doi.org/10.1590/0037-8682-0126-2013
[8] Ahmed, K.,
et al
. (2016) A Second WNT for Old Drugs: Drug Repositioning against
WNT-Dependent Cancers.
Cancers
, 8, 66. https://doi.org/10.3390/cancers8070066
DOI: 10.4236/jbm.2020.85005 50 Journal of Biosciences and Medicines
J. L. Araújo et al.
[9] Rappoport, D. and Furche, F. (2010) Property-Optimized Gaussian Basis Sets for
Molecular Response Calculations.
The Journal of Chemical Physics
, 133, Article ID:
134105. https://doi.org/10.1063/1.3484283
[10] Araújo, J.L.,
et al
. (2019) Estudo in sílico da atividade biológica por docagem
molecular da desloratadina contra esquistossomose.
Revista Eletrônica Acervo Saúde
,
No. 28, e993. https://doi.org/10.25248/reas.e993.2019
[11] Batchelor, T.T.,
et al
. (2007) AZD2171, a Pan-VEGF Receptor Tyrosine Kinase In-
hibitor, Normalizes Tumor Vasculature and Alleviates Edema in Glioblastoma Pa-
tients.
Cancer Cell
, 11, 83-95. https://doi.org/10.1016/j.ccr.2006.11.021
[12] Bruijnincx, P.C.A. and Sadler, P.J. (2008) New Trends for Metal Complexes with
Anticancer Activity.
Current Opinion in Chemical Biology
, 12, 197-206.
https://doi.org/10.1016/j.cbpa.2007.11.013
[13] Rocha, J.A. (2018) Planejamento racional, síntese, caracterização e estudo in silico
de complexos metálicos de rutênio e alcaloides de pilocarpus microphyllus contra a
esquistossomose [tese]. Universidade Federal do Piauí, Teresina.
[14] Berman, H.M.,
et al
. (2000) The Protein Data Bank.
Nucleic Acids Research
, 28,
235-242. https://doi.org/10.1093/nar/28.1.235
[15] Pettersen, E.F.,
et al
. (2004) UCSF Chimera: A Visualization System for Exploratory
Research and Analysis.
Journal of Computational Chemistry
, 25, 1605-1612.
https://doi.org/10.1002/jcc.20084
[16] Araújo, J.L.,
et al
. (2019) Evaluation by Molecular Docking of Inhibitors of the En-
zyme Pteridine Reductase 1 from Leishmania.
Revista Prevenção de Infecção e Saúde
,
5, e9056. https://doi.org/10.26694/repis.v5i0.9056
[17] Frisch, A.E.,
et al
. (2009) Gauss-View, Version 5.0.8. Gaussian, Wallingford.
[18] Kohn, W. and Sham, L.J. (1965) Self-Consistent Equations Including Exchange and
Correlation Effects.
Physical Review
, 140, A1133.
https://doi.org/10.1103/PhysRev.140.A1133
[19] Barone, V.,
et al
. (2002) DFT Calculation of NMR JFF Spin-Spin Coupling Con-
stants in Fluorinated Pyridines.
Journal of Physical Chemistry A
, 106, 5607-5612.
https://doi.org/10.1021/jp020212d
[20] Rocha, J.A.,
et al
. (2018) Computational Quantum Chemistry, Molecular Docking,
and ADMET Predictions of Imidazole Alkaloids of
Pilocarpus microphyllus
with
Schistosomicidal Properties.
PLoS ONE
, 13, e0198476.
https://doi.org/10.1371/journal.pone.0198476
[21] Goodsell, D.S.,
et al
. (1996) Automated Docking of Flexible Ligands: Applications of
AutoDock.
Journal of Molecular Recognition
, 9, 1-5.
https://doi.org/10.1002/(SICI)1099-1352(199601)9:1<1::AID-JMR241>3.0.CO;2-6
[22] Morris, G.M.,
et al
. (1998) Automated Docking Using a Lamarckian Genetic Algo-
rithm and an Empirical Binding Free Energy Function.
Journal of Computational
Chemistry
, 19, 1639-1662.
https://doi.org/10.1002/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.C
O;2-B
[23] Solis, F.J. and Wets, R.J.-B. (1981) Minimization by Random Search Techniques.
Mathematics of Operations Research
, 6, 19-30. https://doi.org/10.1287/moor.6.1.19
[24] Ramos, R.M.,
et al
. (2012) Interaction of Wild Type, G68R and L125M Isoforms of
the Arylamine-n-acetyltransferase from
Mycobacterium tuberculosis
with Isoniazid:
A Computational Study on a New Possible Mechanism of Resistance.
Journal of
Molecular Modeling
, 18, 4013-4024. https://doi.org/10.1007/s00894-012-1383-6
DOI: 10.4236/jbm.2020.85005 51 Journal of Biosciences and Medicines
J. L. Araújo et al.
[25] Carneiro, S.M.P.,
et al
. (2012) The Cytotoxic and Antileishmanial Activity of Ex-
tracts and Fractions of Leaves and Fruits of
Aaadirachta indica
(A juss.).
Biological
Research
, 45, 111-116. https://doi.org/10.4067/S0716-97602012000200002
[26] Bora-tatar, G.,
et al
. (2009) Molecular Modifications on Carboxylic Acid Derivatives
as Potent Histone Deacetylase Inhibitors: Activity and Docking Studies.
Bioorganic
& Medicinal Chemistry
, 17, 5219-5228. https://doi.org/10.1016/j.bmc.2009.05.042
[27] Gourley, D.G.,
et al
. (2001) Pteridine Reductase Mechanism Correlates Pterin Me-
tabolism with Drug Resistance in Trypanosomatid Parasites.
Nature Structural Bi-
ology
, 8, 521-525. https://doi.org/10.1038/88584
[28] Führing, J.,
et al
. (2012) Octamerization Is Essential for Enzymatic Function of
Human UDP-Glucose Pyrophosphorylase.
Glycobiology
, 23, 426-437.
https://doi.org/10.1093/glycob/cws217
[29] Cramer, J.T.,
et al
. (2018) Decoding Allosteric Networks in Biocatalysts: Rational
Approach to Therapies and Biotechnologies.
ACS Catalysis
, 8, 2683-2692.
https://doi.org/10.1021/acscatal.7b03714
[30] Lamerz, A.C.,
et al
. (2006) Molecular Cloning of the
Leishmania major
UDP-Glucose
Pyrophosphorylase, Functional Characterization, and Ligand Binding Analyses Us-
ing NMR Spectroscopy.
The Journal of Biological Chemistry
, 281, 16314-16322.
https://doi.org/10.1074/jbc.M600076200
[31] Rao, S.N.,
et al
. (2007) Validation Studies of the Site-Directed Docking Program
LibDock.
Journal of Chemical Information and Modeling
, 47, 2159-2171.
https://doi.org/10.1021/ci6004299
[32] Warren, G.L.,
et al
. (2006) A Critical Assessment of Docking Programs and Scoring
Functions.
Journal of Medicinal Chemistry
, 49, 5912-5931.
https://doi.org/10.1021/jm050362n
[33] Goncalves, V.,
et al
. (2017) Structure-Guided Optimization of Quinoline Inhibitors
of Plasmodium N-myristoyltransferase.
MedChemComm
, 8, 191-197.
https://doi.org/10.1039/C6MD00531D
[34] Chow, M.,
et al
. (1987) Myristylation of Picornavirus Capsid Protein VP4 and Its
Structural Significance.
Nature
, 327, 482-486. https://doi.org/10.1038/327482a0
[35] Araújo, J.L.,
et al
. (2020) Molecular Docking of Rutenum Complex with Epiisopy-
loturin and Nitric Oxide against Nucleoside Diphosphate Kinase Protein Leishma-
nia.
Research
,
Society and Development
, 9, e59922121.
https://doi.org/10.33448/rsd-v9i2.2121
[36] Lascu, I. and Gonin, P. (2000) The Catalytic Mechanism of Nucleoside Diphosphate
Kinases.
Journal of Bioenergetics and Biomembranes
, 32, 237-246.
https://doi.org/10.1023/A:1005532912212
[37] Souza, T.A.,
et al
. (2011) Molecular Adaptability of Nucleoside Diphosphate Kinase
b from Trypanosomatid Parasites: Stability, Oligomerization and Structural Deter-
minants of Nucleotide Binding.
Molecular BioSystems
, 7, 2189-2195.
https://doi.org/10.1039/c0mb00307g
[38] Parkin, D.W.,
et al
. (1997) Isozyme-Specific Transition State Inhibitors for the Try-
panosomal Nucleoside Hydrolases.
Biochemistry
, 36, 3528-3534.
https://doi.org/10.1021/bi962319v
[39] Parkin, D.W.,
et al
. (1991) Nucleoside Hydrolase from
Crithidia fasciculata
. Meta-
bolic Role, Purification, Specificity, and Kinetic Mechanism.
The Journal of Biolog-
ical Chemistry
, 266, 20658-20665.
[40] Santos, K.K.A.,
et al
. (2012) Trypanocide, Cytotoxic, and Antifungal Activities of
Momordica charantia
.
Pharmaceutical Biology
, 50, 162-166.
https://doi.org/10.3109/13880209.2011.581672
DOI: 10.4236/jbm.2020.85005 52 Journal of Biosciences and Medicines
J. L. Araújo et al.
[41] Prasanna, S. and Doerksen, R.J. (2009) Topological Polar Surface Area: A Useful
Descriptor in 2D-QSAR.
Current Medicinal Chemistry
, 16, 21-41.
https://doi.org/10.2174/092986709787002817
[42] Camacho, M.D.R.,
et al
. (2001) Terpenoids from
Guarea rhophalocarpa
.
Phytoche-
mistry
, 56, 203-210. https://doi.org/10.1016/S0031-9422(00)00310-1
[43] Boeck, P.,
et al
. (2006) Synthesis of Chalcone Analogues with Increased Antileish-
manial Activity.
Bioorganic & Medicinal Chemistry
, 14, 1538-1545.
https://doi.org/10.1016/j.bmc.2005.10.005
[44] Royo, V.A.,
et al
. (2003) Biological Activity Evaluation of Dibenzilbutirolactones
Lignans Derivatives against
Leishmania braziliensis
.
Revista Brasileira de Farma-
cognosia
, 13, 18-21. https://doi.org/10.1590/S0102-695X2003000400007
[45] Araújo, J.L.,
et al
. (2020) Predição computacional de alvos moleculares de um
complexo metálico de rutênio com epiisopiloturina e óxido nítrico.
Revista de
Saúde
, 11, e993.
DOI: 10.4236/jbm.2020.85005 53 Journal of Biosciences and Medicines
