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Study of novel triazolo-benzodiazepine analogues as antidepressants targeting by molecular docking and ADMET properties prediction

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Assia Belhassan at Université Moulay Ismail
Assia Belhassan
Hanane Zaki at Biotechnology, Bioresources and Bioinformatics (3BIO) Laboratory, Sultan Moulay Sliman University
Hanane Zaki
  • Biotechnology, Bioresources and Bioinformatics (3BIO) Laboratory, Sultan Moulay Sliman University
Mohamed Benlyas at Université Moulay Ismail
Mohamed Benlyas
Tahar Lakhlifi at Faculté des Sciences de Meknès
Tahar Lakhlifi
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Abstract and Figures

In this study, we have selected a series of a new family of molecules bearing Triazolo-benzodiazepines, an eleven membered heterocyclic ring has been studied for antidepression activity. Docking studies suggested that all the eleven ligands interacted well within active site of Drosophila melanogaster dopamine transporter (dDAT) (PDB ID: 4M48). Most ligands formed H-bond with amino acid Phe43, Asp46, Asp475, Tyr123, Ser421 and/or Gln316 and also exhibited Pi and Pi-Pi interactions with amino acid residues Tyr124, Phe319, Phe43, Phe325, Ala479 and Val120. In silico ADME evaluations of compounds showed more than 96% intestinal absorption for all compounds. During in vitro Toxicity properties prediction, the Triazolo-benzodiazepines derivatives: M1, M2, M3 and M11 showed less toxicity than the other studied molecules against algae, for daphnia the molecules M1, M2, M3, M8, M10 and M11 showed less toxicity than the reference molecule (Nortriptyline).
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Study of novel triazolo-benzodiazepine analogues as antidepressants
targeting by molecular docking and ADMET properties prediction
Assia Belhassan
a
,
b
, Hanane Zaki
b
,
c
, Mohamed Benlyas
c
, Tahar Lakhlifi
a
,
Mohammed Bouachrine
a
,
b
,
*
a
MCNS Laboratory, Faculty of Science, Moulay Ismail University, Meknes, Morocco
b
Materials, Environment &Modeling Laboratory, High School of Technology, Moulay Ismail University, Meknes, Morocco
c
Biology Environment and Health Laboratory, Faculty of Science and Technics, Moulay Ismail University, Errachdia, Morocco
ARTICLE INFO
Keywords:
Theoretical chemistry
Pharmaceutical chemistry
Bioinformatics
Biochemistry
Triazolo-benzodiazepine
Antidepressant activity
Molecular docking
ADMET properties
Nortriptyline
ABSTRACT
In this study, we have selected a series of a new family of molecules bearing Triazolo-benzodiazepines, an eleven
membered heterocyclic ring has been studied for antidepression activity. Docking studies suggested that all the
eleven ligands interacted well within active site of Drosophila melanogaster dopamine transporter (dDAT) (PDB
ID: 4M48). Most ligands formed H-bond with amino acid Phe43, Asp46, Asp475, Tyr123, Ser421 and/or Gln316
and also exhibited Pi and Pi-Pi interactions with amino acid residues Tyr124, Phe319, Phe43, Phe325, Ala479 and
Val120. In silico ADME evaluations of compounds showed more than 96% intestinal absorption for all com-
pounds. During in vitro Toxicity properties prediction, the Triazolo-benzodiazepines derivatives: M
1
,M
2
,M
3
and
M
11
showed less toxicity than the other studied molecules against algae, for daphnia the molecules M
1
,M
2
,M
3
,
M
8
,M
10
and M
11
showed less toxicity than the reference molecule (Nortriptyline).
1. Introduction
Diazepines are a well-known class of heterocycles and they have
gained importance since 1957, when the chlordiazepoxide (first benzo-
diazepine) was synthesized and studied in terms of psychotropic activity
[1,2,3]. Actually, they possess a wide spectrum of biological activity
including anxiolytic, hypnotic, sedative, anticonvulsant, skeletal,
amnestic and muscle relaxant properties [4,5,6,7].
Triazolo-benzodiazepines analogues are a key structural motif in
numerous therapeutics that have sedative, muscle relaxant, and anti-
tumor activities [8,9]. Alprazolam, adinazolam and estazolam are
commercially available chemical drugs based on triazolo-benzodiazepine
scaffold that widely used as anxiolytic and sedative agents [10,11,12,
13]. Some triazolo-benzodiazepine derivatives have been reported to be
weakly bound to the benzodiazepine receptor and prevent serine prote-
ase [14,15].
So, due to the therapeutic and biological applications of this class of
compounds, the study of type of interactions between these molecules
and protein targetingby molecular docking methods for the prediction of
the activity is definitely of great importance.
Molecular docking turns out to be a reliable method for preliminary
evaluation of binding affinity and prediction of intermolecular in-
teractions of novel compounds with receptors [16]. Nowadays, this
method has become indispensable for studying protein-ligand in-
teractions. Docking method can produce significant knowledge for
complex systems, which complements experimentally achievable data.
Molecular docking simulations have found widespread application for
virtual screening and pose prediction of new or non-synthesized com-
pounds [17,18,19,20].
Molecular docking studies were focused on the dopamine trans-porter
(DAT). This transmembrane protein is responsible for reup-take of
dopamine from the synaptic cleft. DAT inhibitors are used in the treat-
ment of depression due to the increased level of dopamine in the synaptic
cleft as well as in adjuvant therapy of Parkinson's Disease (PD) [21].
In this paper, a new family of Triazolo-benzodiazepines (Fig. 1) was
docked to neurotransmitter trans-porter (DAT). We predict and interpret
thebinding affinity and intermolecular interactions of complexes formed
by docking of these molecules on DAT protein, so as to gain insight if
those newly synthesized compounds could be of use as therapeutics in
medicine.
* Corresponding author.
E-mail address: m.bouachrine@est-umi.ac.ma (M. Bouachrine).
Contents lists available at ScienceDirect
Heliyon
journal homepage: www.heliyon.com
https://doi.org/10.1016/j.heliyon.2019.e02446
Received 9 July 2019; Received in revised form 24 August 2019; Accepted 4 September 2019
2405-8440/©2019 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
Heliyon 5 (2019) e02446
2. Material and methods
2.1. Data collection
2.1.1. Ligands
In the present study, a series of 11 selected Triazolo-benzodiazepines
derivatives were taken from literature (Table 1)[22], these molecules
were considered to molecular docking study. The selected
Triazolo-benzodiazepines were prepared by Asgari et al. from simple
methods and substrates [22].
2.1.2. Receptor: dopamine transporter DAT
The dopamine trans-porter (DAT) is transmembrane protein.
Drosophila melanogaster dopamine transporter (dDAT) is a proven
model of DAT, which is 50% similar to mammalian DAT sequence, and is
used in research into the mechanism of action of many compounds. Thus,
in our docking studies we made use of the X-ray structure of dDAT in
complex with the tricycilcanitide-pressant nortriptyline, which indicate
primary binding site (PDB code: 4M48) [16].
2.2. Molecular docking studies
Molecular docking turns out to be a reliable method for pre-liminary
evaluation of binding affinity and prediction of intermolecular in-
teractions of novel compounds with receptors. We decided to use
neurotrans-mitter transporters (DAT) for docking study. In general, our
research is based on crystal structures of receptors with bound ligand
molecules. This structure has been obtained from X-ray crystal data of
RCSB Protein Data Bank (PDB). In the majority of selected structures, co-
crystallized ligand molecules are known drugs with proven action, and
thus determine the binding site location in DAT as well as serve as ref-
erences in our considerations.
In this research space, a docking process is launched for each studied
molecule; the bioactive conformations were simulated using Autodock
vina and Autodock tools 1.5.6 [23]. The results were analyzed using
Discovery studio 2016 [24] and PyMol [25] softwares.
2.3. ADME and toxicity prediction
Absorption, distribution, metabolism, excretion and toxicity are pre-
dicted for the 11 selected Triazolo-benzodiazepines derivatives using Pre
ADMET predictor server [26,27].
3. Results and discussion
3.1. Molecular docking
The top-scoring pose of each molecule is selected according to the
best interaction energy with the Drosophila melanogaster dopamine
transporter (dDAT) (Table 2).
The best energies of interaction with the Drosophila melanogaster
dopamine transporter (dDAT) (lowest energy level) are observed for the
ligand M
10
, whereas the ligand M
6
is the least stable ligand in the list of
studied molecules (Table 2). We can also observe that all complex formed
by studied compounds and dDAT are more stable than the complex
formed with the reference molecule (Nortriptyline) except for two
studied molecules: M
2
and M
6
.
The result of the re-docked Nortriptyline molecule and its position in
the PDB structure of protein dDAT is shown in Fig. 2.
Nortriptyline is involved in Pi-Pi T-shaped interactions with Tyr124
as well as alkyl and Pi-alkyl interactions with Ala479, and Pi-sigma in-
teractions with Val120. The N-methylpropanamine chain of nortriptyline
enables formation of carbon hydrogen bonds with Asp46, Ser421 and
Phe319, while conventional hydrogen bon and Pi-donor hydrogen bond
are created only with Phe43 because nitrogen atom (N) is present in this
position. The Van der Waals interactions are observed with Ile 483, Tyr
Fig. 1. Chemical structures of studied compounds.
Table 1
Chemical structures of the 11 selected Triazolo-benzodiazepines derivatives.
NRR
1
R
2
R
3
1 Cyclohexyl O–CH
3
HH
2 Cyclohexyl O–CH
3
O–CH
3
H
3 Cyclohexyl Cl H H
4t-Butyl CH
3
HH
5t-Butyl H H CH
3
6t-Butyl O–CH
3
HH
7t-Butyl O–CH
3
O–CH
3
H
8t-Butyl Cl H H
9t-Butyl H H F
10 Cyclohexyl F H H
11 1,1,3,3-tetramethyl-butyl F H H
Table 2
Comparison of Autodock score (kcal/mol) of the 9 best poses obtained by docking of 11 selected Triazolo-benzodiazepines derivatives and the re-docking of reference
molecule (Nortriptyline) with dDAT.
Ligands 123456789
Ref: Nortriptyline -10.0 -9.3 -9.2 -9.0 -8.8 -8.7 -8.7 -8.5 -8.0
M
1
-10.0 -9.8 -9.2 -9.1 -9.0 -8.9 -8.8 -8.7 -8.7
M
2
-9.9 -9.5 -9.4 -9.2 -9.1 -8.9 -8.9 -8.8 -8.7
M
3
-10.6 -10.0 -10.0 -9.9 -9.8 -9.6 -9.5 -9.4 -9.4
M
4
-10.5 -9.4 -9.3 -9.3 -9.3 -9.2 -9.2 -9.1 -8.8
M
5
-10.4 -9.3 -9.3 -9.3 -9.1 -8.7 -8.7 -8.7 -8.6
M
6
-9.6 -9.2 -9.1 -9.1 -9.0 -9.0 -8.9 -8.9 -8.7
M
7
-10.0 -9.9 -9.5 -9.5 -9.4 -9.2 -9.0 -9.0 -8.9
M
8
-10.4 -9.8 -9.5 -9.4 -9.4 -9.3 -9.3 -9.2 -8.9
M
9
-10.3 -9.4 -9.4 -9.3 -9.3 -9.1 -9.0 -8.9 -8.8
M
10
-12.3 -10.6 -10.5 -10.3 -10.0 -10.0 -9.8 -9.6 -9.5
M
11
-10.1 -10.1 -9.9 -9.5 -9.3 -9.1 -8.8 -8.8 -8.7
A. Belhassan et al. Heliyon 5 (2019) e02446
2
123 and Gly 425 amino acids.
The docking result of 11 selected Triazolo-benzodiazepines de-
rivatives and dDAT is shown in Fig. 3. And the comparison of these re-
sults and the result of the re-docked Nortriptyline molecule and its
position in the PDB structure of protein dDAT is shown in Table 3.
Visual inspection of the docked poses of molecule M
11
clearly in-
dicates similarity between binding modes and interactions of this mole-
cule and the reference molecule (Nortriptyline) with dDAT. Both of them
form carbon hydrogen bonds with Asp46, while conventional hydrogen
hydrogen bond is formed with Phe43. Moreover, Tyr124 is bonded with
M
3
,M
4
,M
5
,M
7
,M
8
,M
9
and M
9
by Pi-Pi interactions, which play a similar
role in the binding of docked Nortriptyline molecule. All orientations of
the discussed Triazolo-benzodiazepines derivatives are stabilized in the
dDAT cavity by weak hydrophobic interactions with Val120 and Ala479
in a similar manner to docked Nortriptyline except the two molecules M
5
and M
9
.
The similarities between interactions of 11 Triazolo-benzodiazepines
derivatives and reference molecule are retained to usas therapeutics in
medicine to treat the depression.
3.2. ADME, toxicity and drug likeness prediction
Absorption, distribution, metabolism, excretion, toxicity and drug
likeness are predicted for the 11selected Triazolo-benzodiazepines de-
rivatives using Pre ADMET predictor server, and the results are presented
in Tables 4and 5.
The analysis of predicted ADME properties results (Table 4) shows
that: the eleven molecules have different predicted in vivo blood-brain
barrier penetration, the molecules M
1
,M
2
,M
3
and M
10
have highest
penetration (0.318, 0.320, 0.340 and 0.331, respectively) in comparison
with the other molecules, whereas the molecule M
4
has a very low
permeability (0.122). All these values are largely insufficient; in fact
blood-brain barrier penetration of antidepressant molecules can reach for
example in Nortriptyline 13.406.
All the molecules can't inhibit or be substrate for cytochromes
CYP_2C19, CYP_2C9 and CYP_2D6 while they inhibit and substrate cy-
tochrome CYP_3A4. These molecules have a high absorption which can
exceed 96% for all the molecules, which is important for oral adminis-
tration. A percent of plasma proteinbinding more than 80% is noted for
all molecules which mean that 20% of the fraction of these molecules can
actually give the pharmacological effect. This doesn't prevent that pro-
tein binding can influence the drug's biological half-life. The bound
portion may act as a reservoir or depot from which the drug is slowly
released as the unbound form.
The results of the prediction of the toxicity presented in Table 5 show
that these molecules show a very low toxicity on the algae and daphnia,
and a negative toxicity according to the four Ames tests (in vitro Ames
test in TA100 strain (Metabolic activation by rat liver homogenate), in
vitro Ames test in TA100 strain (No metabolic activation), in vitro Ames
test in TA1535 strain (Metabolic activation by rat liver homogenate), in
vitro Ames test in TA1535 strain (No metabolic activation)) except M
4
,
M
5
,M
6
,M
7
,M
8
and M
9
whom has a positive toxicity on in vitro Ames test
in TA100 strain (Metabolic activation by rat liver homogenate).
The Ames's mutagenicity test that uses several strains of the bacte-
rium Salmonella typhimurium that carry mutations in genes involved in
histidine synthesis, so that they require histidine for growth show that
the molecule M
2
can induce mutations, and none of these molecules
present a risk of carcinogenicity neither in the rat nor in the mouse, and
Fig. 2. Types of interactions between the dDAT (PDB code: 4M48) and Nortriptyline.
A. Belhassan et al. Heliyon 5 (2019) e02446
3
Fig. 3. Types of interactions between the dDAT (PDB code: 4M48) and the 11 selected Triazolo-benzodiazepines derivatives.
A. Belhassan et al. Heliyon 5 (2019) e02446
4
Table 3
Comparison of interactions formed by docking of 11 selected Triazolo-benzodiazepines derivatives and the re-docking of reference molecule (Nortriptyline) with dDAT.
Type of interactions Residues Molecules
Ref: Nortriptyline M
1
M
2
M
3
M
4
M
5
M
6
M
7
M
8
M
9
M
10
M
11
Hydrogen
Bonds
Conventional
H-Bond
PHE43 X X
GLN316 X
ASP46 X X X
TYR123 X X X
SER421 X
ASP475 X
Carbon -H-Bond SER421 X X X X
ASP46 X X X
PHE319 X X
ALA479 X
SER320 X
ASP475 X
TYR123 X
ALA44 X
SER124 X
Pi-Donor-H-Bond PHE43 X
Hydrophobic
interactions
Pi-Pi TYR124 X X X X X X X X
PHE319 X X X X X
PHE43 X X
PHE325 X
Alkyl VAL120 X X X X X
ALA479 X
ILE483 X
ILE127 X
ARG52 X X
ALA44 X X
ALA48 X
TYR124 X
Pi-Alkyl ALA479 X X X X
PHE319 X X X
PHE325 X
TRP51 X X
TYR123 X
TYR124 X X X
PHE471 X
VAL120 X
Pi-Sigma VAL120 X X X X X X X
PHE43 XX
Table 4
Predicted ADME properties of the 11 studied compounds in comparison with the reference drug.
Ref M
1
M
2
M
3
M
4
M
5
M
6
M
7
M
8
M
9
M
10
M
11
BBB 13.406 0.318 0.320 0.340 0.122 0.159 0.245 0.197 0.277 0.180 0.331 0.246
BS 66.488 93.970 52.011 59.350 247.204 77.602 326.688 181.526 206.459 368.859 189.694 157.659
CYP_2C19_inhibition Inhibitor Non Non Non Non Non Non Non Non Non Non Non
CYP_2C9_inhibition Non Non Non Non Non Non Non Non Non Non Non Non
CYP_2D6_inhibition Inhibitor Non Non Non Non Non Non Non Non Non Non Non
CYP_2D6_substrate Substrate Non Non Non Non Non Non Non Non Non Non Non
CYP_3A4_inhibition Non Inhibitor Inhibitor Inhibitor Inhibitor Inhibitor Inhibitor Inhibitor Inhibitor Inhibitor Inhibitor Inhibitor
CYP_3A4_substrate Non Weakly Substrate Weakly Substrate Substrate Substrate Substrate Substrate Substrate Weakly Substrate
HIA 100 96.828 97.356 96.548 96.466 96.466 97.004 97.525 96.457 96.506 96.438 96.440
MDCK 96.879 1.121 0.143 3.675 24.933 112.593 6.772 1.476 9.663 27.802 2.223 0.043
Pgp_I Inhibitor Non Inhibitor Inhibitor Non Non Inhibitor Inhibitor Inhibitor Non Non Inhibitor
PPB 100 90.524 89.190 91.919 88.306 87.741 83.385 80.719 87.854 88.330 89.897 89.716
PWS 2.941 2.472 1.721 0.520 9.662 18.801 22.013 15.382 4.624 21.762 1.755 0.514
SKlogD_value 3.500 3.554 3.5489 4.269 3.407 3.3850 2.876 2.872 3.592 3.046 3.735 4.600
SKlogP_value 4.844 3.554 3.5489 4.269 3.407 3.3850 2.876 2.872 3.592 3.046 3.735 4.600
SKlogS_buffer -3.621 -3.676 -3.961 -3.880 -3.213 -3.716 -3.109 -3.394 -3.312 -3.043 -3.359 -3.468
SKlogS_pure -4.975 -5.256 -5.441 -5.938 -4.621 -4.332 -4.280 -4.466 -4.962 -4.272 -5.393 -5.955
BBB ¼in vivo blood-brain barrier penetration (C.brain/C.blood), BS ¼Buffer Solubility (mg/l), CYP2C19 ¼cytochrome P4502C19, CYP2C9 ¼cytochrome P4502C9,
CYP3A4 ¼cytochrome P4503A4, CYP2D6 ¼cytochrome CYP2D6, PgP I ¼P-glycoprotein inhibition, PPB ¼Plasma Protein Binding %, PWS ¼Pure Water Solubility
(mg/l), HIA ¼Human intestinal absorption %, MDCK ¼in vitro MDCKcellpermeability (Mandin Darby Canine Kidney (nm/sec)).
A. Belhassan et al. Heliyon 5 (2019) e02446
5
all present a medium risk to inhibit HERG (Human ether-a-go-go related
gene channel). It should be noted that all these values are predicted.
4. Conclusion
In this study, the docking study was performed to elucidate the type of
interactions between 11 selected Triazolo-benzodiazepines derivatives
and Drosophila melanogaster dopamine transporter (dDAT), the results
show that all the eleven ligands interacted well within active site of dDAT
(PDB ID: 4M48); the molecules showed promising in silico results as
indicated by their high protein–ligand interaction energy. The studied
compounds are screened by ADME and Toxicity properties; these mole-
cules are predicted to have more than 96% intestinal absorption for all
compounds. During in vitro Toxicity properties prediction, the Triazolo-
benzodiazepines derivatives: M
1
,M
2
,M
3
,M
8
,M
10
and M
11
showed less
toxicity than the reference molecule (Nortriptyline) against daphnia.
A deep investigation of in vitro activity supported by docking results
and in silico ADMET results clearly suggested that these molecules could
be of use as therapeutics in medicine to treat the depression.
Declarations
Author contribution statement
Mohammed Bouachrine, Assia Belhassan, Hanane Zaki, Mohamed
Benlyas, Tahar Lakhlifi: Conceived and designed the experiments; Per-
formed the experiments; Analyzed and interpreted the data; Contributed
reagents, materials, analysis tools or data; Wrote the paper.
Funding statement
This research did not receive any specific grant from funding agencies
in the public, commercial, or not-for-profit sectors.
Competing interest statement
The authors declare no conflict of interest.
Additional information
No additional information is available for this paper.
Acknowledgements
We are grateful to the “Association Marocaine des Chimis-
tesTh
eoriciens”(AMCT) for its pertinent help concerning the programs.
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ID Ref M
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M
2
M
3
M
4
M
5
M
6
M
7
M
8
M
9
M
10
M
11
algae_at 0.008 0.019 0.013 0.011 0.053 0.064 0.055 0.040 0.037 0.076 0.025 0.011
Ames_test Mutagen Mutagen Non-mutagen Mutagen Mutagen Mutagen Mutagen Mutagen Mutagen Mutagen Mutagen Mutagen
Carcino_Mouse Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative
Carcino_Rat Positive Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative
daphnia_at 0.030 0.024 0.022 0.009 0.0434 0.044 0.078 0.070 0.029 0.059 0.020 0.012
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TA100_10RLI Negative Negative Negative Negative Positive Positive Positive Positive Positive Positive Negative Negative
TA100_NA Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative
TA1535_10RLI Positive Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative
TA1535_NA Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative
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A. Belhassan et al. Heliyon 5 (2019) e02446
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... Additionally, in the existing biomedical scenario, the in-silico computer-aided drug designing (CADD) concept is being deployed to succor and expedite hit identification, assort lead from the hit, screen out massive amounts of compound libraries into compact clusters of predicted bioactive candidates (thus optimizing the ADMET [absorption, distribution, metabolism, excretion and toxicity] profile), and evade obstacles related to safety. CADD utilizes various methods for the in-silico predictions, including: physicochemical, pharmacokinetic, bioactivity [42], ADMET [43,44], drug likeness predictions, and Lipinski's rule of 5 (RO5) [45][46][47]. Enormous in-silico ADMET techniques and software have been successfully developed and examined [48][49][50][51]. ...
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... Although L28 and L30 ligands are engineered as potent inhibitors with a favorable ADMET profile, thus we have studied their intermolecular interactions towards the drosophila melanogaster dopamine transporter (DAT) of 4M48. pdb code, as a transmembrane protein able to extract the neurotransmitter dopamine out of the synaptic cleft and transfer it into the cytosol of neighboring cells [6,[54][55][56]. The molecular docking simulations of (L28, L30-protein) complexes were done in the active sites of tricyclic antidepressant nortriptyline (as co-crystallized ligand linked to the targeted protein in his A-chain) which resulted from the ProteinsPlus online server [57], like Tyr124 A, Phe325 A, and Phe43 A amino acids, as presented in Fig. 6. ...
QSAR, ADME-Tox, molecular docking and molecular dynamics simulations of novel selective glycine transporter type 1 inhibitors with memory enhancing properties
Article
Full-text available
  • Feb 2023
A structural class of forty glycine transporter type 1 (GlyT1) inhibitors, was examined using molecular modeling techniques. The quantitative structure-activity relationships (QSAR) technology confirmed that human GlyT1 activity is strongly and significantly affected by constitutional, geometrical, physicochemical and topological descriptors. ADME-Tox in-silico pharmacokinetics revealed that L28 and L30 ligands were predicted as non-toxic inhibitors with a good ADME profile and the highest probability to penetrate the central nervous system (CNS). Molecular docking results indicated that the predicted inhibitors block GlyT1, reacting specifically with Phe319, Phe325, Tyr123, Tyr 124, Arg52, Asp475, Ala117, Ala479, Ile116 and Ile483 amino acids of the dopamine transporter (DAT) membrane protein. These results were qualified and strengthened using molecular dynamics (MD) study, which affirmed that the established intermolecular interactions for (L28, L30–DAT protein) complexes remain perfectly stable along 50 ns of MD simulation time. Therefore, they could be strongly recommended as therapeutics in medicine to improve memory performance.
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... Additionally, in the existing biomedical scenario, the in-silico computer-aided drug designing (CADD) concept is being deployed to succor and expedite hit identification, assort lead from the hit, screen out massive amounts of compound libraries into compact clusters of predicted bioactive candidates (thus optimizing the ADMET [absorption, distribution, metabolism, excretion and toxicity] profile), and evade obstacles related to safety. CADD utilizes various methods for the in-silico predictions, including: physicochemical, pharmacokinetic, bioactivity [42], ADMET [43,44], drug likeness predictions, and Lipinski's rule of 5 (RO5) [45][46][47]. Enormous in-silico ADMET techniques and software have been successfully developed and examined [48][49][50][51]. ...
DFT and In-silico Investigations along with In-vitro Antitumor and Antimicrobial Assessments of Pharmacological Molecules
Article
Full-text available
  • Sep 2022
  • CURR ORG SYNTH
Background Molecules, bearing an active methylene bridge, are deemed to be one of the most fruitful and remarkable precursors that have been incorporated in the synthetic strategy of an assortment of bioactive compounds. Objective The reactive methylene derivatives have been endowed with multiple reactions, which target biological and medicinal applications and are resultant from their structural multiplicity and discrete reactivity. Methods The present report endeavors to synthesize, characterize, and in-vitro evaluate several novel propanoic acid, coumarin, and pyrazole derivatives as antimicrobial and antiproliferative agents. The in-silico molecular docking, physicochemical, pharmacokinetic/ADMET, bioactivity, and drug likeness predictions were conducted for all the synthesized compounds. Results The highest docking score is -9.9 and -8.3 kcal/mol respectively for compound 9 (azo-coumarin) and 13 (acrylic acid derivative) with the target proteins E. coli topoisomerase II, DNA gyrase subunit B and PI3K p110α domain, respectively. Moreover, this study predicts the synthesized molecules that may inhibit the novel COVID-19, obtained through virtual screenings only, where compounds 9, 13, 14, 17, and 19 came to the limelight with good docking scores i.e more than 8 Kcal/mol. Safety profiling of the most potent compound 9 was utilized against normal cell line and hemolytic effect on RBCs. Conclusion The in-silico ADMET studies of the synthesized compounds revealed moderate to good drug likeness, high gastro intestinal (GI) absorption, inhibits the Cytochrome CYP2C19 and CYP2C9 and all the derivatives possess non-cancerous nature. The in-vitro screening demonstrated that several of the novel molecules are promising drug candidates. The density function theory (DFT) theoretical calculations were performed to calculate the energy levels of the FMOs and their energy gabs, dipole moment as well as the molecular electrostatic potential. Such parameters along with the physicochemical parameters could be good tool to confirm the biological activity.
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... Molecular docking results are focused on the dopamine transporter (DAT) bound to the tricyclic antidepressant nortriptyline, as a transmembrane protein that removes the neurotransmitter dopamine from the synaptic cleft and transports it into the cytosol of surrounding cells. The crystal structure of this receptor is extracted using the X-ray diffraction method at a resolution of 2.96 Å taken from the protein data base (PDB) [34][35][36]. In this part of the research, the molecular docking process is started for the following most active molecules (L6, L9, L30, L31 and L37) to predict the type of Intermolecular interactions established with the protein encoded 4M48, compared to the established interactions with the co-crystallized ligand (nortriptyline) pictured in Figure 7, which indicate that Phe43A, Phe325A and Tyr124A amino acids, are the active sites of the target protein, as sourced using the ProteinsPlus online server [37]. ...
pharmaceuticals-15-00670 (2)
Article
Full-text available
  • May 2022
Forty-four bicyclo ((aryl) methyl) benzamides, acting as glycine transporter type 1 (GlyT1) inhibitors, are developed using molecular modeling techniques. QSAR models generated by multiple linear and non-linear regressions affirm that the biological inhibitory activity against the schizophrenia disease is strongly and significantly correlated with physicochemical, geometrical and topological descriptors, in particular: Hydrogen bond donor, polarizability, surface tension, stretch and torsion energies and topological diameter. According to in silico ADMET properties, the most active ligands (L6, L9, L30, L31 and L37) are the molecules having the highest probability of penetrating the central nervous system (CNS), but the molecule 32 has the highest probability of being absorbed by the gastrointestinal tract. Molecular docking results indicate that Tyr124, Phe43, Phe325, Asp46, Phe319 and Val120 amino acids are the active sites of the dopamine transporter (DAT) membrane protein, in which the most active ligands can inhibit the glycine transporter type 1 (GlyT1). The results of molecular dynamics (MD) simulation revealed that all five inhibitors remained stable in the active sites of the DAT protein during 100 ns, demonstrating their promising role as candidate drugs for the treatment of schizophrenia.
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... Molecular docking results are focused on the dopamine transporter (DAT) bound to the tricyclic antidepressant nortriptyline, as a transmembrane protein that removes the neurotransmitter dopamine from the synaptic cleft and transports it into the cytosol of surrounding cells. The crystal structure of this receptor is extracted using the X-ray diffraction method at a resolution of 2.96 Å taken from the protein data base (PDB) [34][35][36]. In this part of the research, the molecular docking process is started for the following most active molecules (L6, L9, L30, L31 and L37) to predict the type of Intermolecular interactions established with the protein encoded 4M48, compared to the established interactions with the co-crystallized ligand (nortriptyline) pictured in Figure 7, which indicate that Phe43A, Phe325A and Tyr124A amino acids, are the active sites of the target protein, as sourced using the ProteinsPlus online server [37]. ...
QSAR, ADMET In Silico Pharmacokinetics, Molecular Docking and Molecular Dynamics Studies of Novel Bicyclo (Aryl Methyl) Benzamides as Potent GlyT1 Inhibitors for the Treatment of Schizophrenia
Article
Full-text available
  • May 2022
Forty-four bicyclo ((aryl) methyl) benzamides, acting as glycine transporter type 1 (GlyT1) inhibitors, are developed using molecular modeling techniques. QSAR models generated by multiple linear and non-linear regressions affirm that the biological inhibitory activity against the schizophrenia disease is strongly and significantly correlated with physicochemical, geometrical and topological descriptors, in particular: Hydrogen bond donor, polarizability, surface tension, stretch and torsion energies and topological diameter. According to in silico ADMET properties, the most active ligands (L6, L9, L30, L31 and L37) are the molecules having the highest probability of penetrating the central nervous system (CNS), but the molecule 32 has the highest probability of being absorbed by the gastrointestinal tract. Molecular docking results indicate that Tyr124, Phe43, Phe325, Asp46, Phe319 and Val120 amino acids are the active sites of the dopamine transporter (DAT) membrane protein, in which the most active ligands can inhibit the glycine transporter type 1 (GlyT1). The results of molecular dynamics (MD) simulation revealed that all five inhibitors remained stable in the active sites of the DAT protein during 100 ns, demonstrating their promising role as candidate drugs for the treatment of schizophrenia.
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... For the treatment of epileptic seizures, there is an everincreasing demand for research into novel compounds with fewer toxicities and side effects.There are various reports on docking studies of benzodiazepine containing heterocycles viz. traizole, pyrimidine, quinazoline [3][4]. The objective of the present investigation is to identify new active compounds for the target protein, GABARAP using the structure-based virtual screening. ...
Molecular Modelling of 1H-Benzo [b] [1,5] Diazepine-2(3H)-one Derivatives and Docking Studies Against Receptor Associated Protein
Article
Full-text available
  • Mar 2022
In the present investigation, some N1-benzoyl/ N1-(1,3,4-thiadiazol-2-yl amino acetyl) -7-substituted- 4-methyl-1,5-benzodiazepine-2-one were designed and docked at active site of cavity 1# of GABA-A receptor associated protein (1KJT) to distinguish from their hypothetical binding mode. The X-ray crystal structure of mammalian GABA-A receptor associated protein (1KJT) obtained from protein data bank was used as target protein. In this investigation the comparative analysis of the docking experiments of modelled compounds with known GABA agonist, Lofendazam was carried out. The dock scores calculated for Lofendazam was -4.7373. Among the modelled compounds, following conformation were found to have lower dock scores as indicated in bracket in comparison to other confermers; N1-benzoyl-7- bromo- 4-methyl-1,5-benzodiazepine-2-one, conformer_C3 (-5.0915), N1-(1,3,4-thiadiazol-2-yl amino acetyl) -7-chloro-4-methyl-1,5-benzodiazepine-2-one, Conformer_C2 (-4.6532). These conformers have more affinity for active site of GABA-A receptor associated protein than other molecules.
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The study of antidepressant properties of new 1,2,3-triazolo-1,4-benzodiazepine derivatives
Article
Full-text available
  • Mar 2024
Anxiety-depressive disorders are among the most common mental health conditions and often cause significant functional impairment, affecting a person’s quality of life. Research conducted in recent years indicate the importance of studying and searching for new substances based on benzodiazepines, in particular triazolobenzodiazepines, for the treatment of anxiety states and disorders, as well as determining the presence of other biological activities of these compounds. Aim. To study the antidepressant activity of new derivatives of 1,2,3-triazolo-1,4-benzodiazepines in the Porsolt forced swim and tail suspension tests. Materials and methods. The antidepressant activity of new 1,2,3-triazolo-1,4-benzodiazepine derivatives under the code MA-252, MA-253, MA-254, MA-255 and MA-261 was studied in the Porsolt forced swim and tail suspension tests. The following behavioral reactions, such as the latent period of the first immobility (more than 5 seconds), the total duration of immobility (staying in a stationary state), the number of immobile episodes, were recorded. Results and discussion. During the study, a decrease in the total duration of immobility, the main indicator of “despair” of animals, and an increase in the latent period of the first immobility were monitored. It may indicate the manifestation of antidepressant properties of new 1,2,3-triazolo-1,4-benzodiazepine derivatives. The indicator of the antidepressant activity in groups of animals administered MA-253, MA-254 and MA-255 derivatives in all doses was higher among the groups studied. The depression index was the lowest when MA-253 and MA-254 derivatives were used in the dose of 1 mg/kg, and was not statistically significantly different from that in the group receiving imipramine in the dose of 25 mg/kg. According to the results of the tail suspension test, 1,2,3-triazolo-1,4-benzodiazepine derivatives MA-253, MA-254 and MA-255 showed a significant decrease in the total duration of immobilization by 69.4 %, 47.1 % and 33.1 %, respectively, in relation to the control group (p<0.05), as well as an increase in the latent period of the onset of the first immobility episode by several times. Conclusions. A decrease in the duration of immobility in mice injected with 1,2,3-triazolo-1,4-benzodiazepine derivatives gives grounds to draw a conclusion that animals develop a state of “behavioral despair” and exhibit antidepressant properties.
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Application of nanofiber-based drug delivery systems in improving anxiolytic effect of new 1,2,3-triazolo-1,4-benzodiazepine derivatives
Article
Full-text available
  • Jan 2024
  • EUR J PHARM SCI
Anxiety disorders are highly prevalent worldwide and can affect people of all ages, genders and backgrounds. Much efforts and resources have been directed at finding new anxiolytic agents and drug delivery systems (DDSs) especially for cancer patients to enhance targeted drug delivery, reduce drug adverse effects, and provide an analgesic effect. The aim of this study was (1) to design and develop novel nanofiber-based DDSs intended for the oral administration of new 1,2,3-triazolo-1,4-benzodiazepines derivatives, (2) to investigate the physical solid-state properties of such drug-loaded nanofibers, and (3) to gain knowledge of the anxiolytic activity of the present new benzodiazepines in rodents in vivo. The nanofibers loaded with 1,2,3-triazolo-1,4-benzodiazepine derivatives were prepared by means of electrospinning (ES). Field-emission scanning electron microscopy and attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy were used for the physicochemical characterization of nanofibers. The anxiolytic activity of new derivatives and drug-loaded nanofibers was studied with an elevated plus maze test and light-dark box test. New 1,2,3-triazolo-1,4-benzodiazepine derivatives showed a promising anxiolytic effect in mice with clear changes in behavioral reactions in both tests. The nanofiber-based DDS was found to be feasible in the oral delivery of the present benzodiazepine derivatives. The nanofibers generated by means of ES presented the diameter in a nanoscale, uniform fiber structure, capacity for drug loading, and the absence of defects. The present findings provide new insights in the drug treatment of anxiety disorders with new benzodiazepine derivatives.
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Palladium-Catalyzed C-N Coupling in the Synthesis of 1,4-Benzodiazepines Fused with 5-Membered Carbo- and Heterocycles
Article
  • Dec 2022
In this review, we have focused our attention on Pd-catalyzed amination and arylation reactions for the construction of various benzodiazepine scaffolds. It includes numerous types of synthetic strategies like C-H arylation, Pd-catalyzed carbonylation, and Buchwald Hartwig coupling. To synthesize different functionalized benzodiazepines, the domino processes as intra- or intermolecular reactions are developed as an eco-friendly and effective tool. Benzodiazepines exhibit several biological activities and play a valuable role in medicinal and pharmaceutical chemistry. This review article mainly focuses on synthesizing a 1,4-benzodiazepine nucleus fused with 5-membered carbo- and heterocycles in the presence of palladium catalysts.
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D3R Grand Challenge 2: blind prediction of protein–ligand poses, affinity rankings, and relative binding free energies
Article
Full-text available
  • Jan 2018
  • J COMPUT AID MOL DES
The Drug Design Data Resource (D3R) ran Grand Challenge 2 (GC2) from September 2016 through February 2017. This challenge was based on a dataset of structures and affinities for the nuclear receptor farnesoid X receptor (FXR), contributed by F. Hoffmann-La Roche. The dataset contained 102 IC50 values, spanning six orders of magnitude, and 36 high-resolution co-crystal structures with representatives of four major ligand classes. Strong global participation was evident, with 49 participants submitting 262 prediction submission packages in total. Procedurally, GC2 mimicked Grand Challenge 2015 (GC2015), with a Stage 1 subchallenge testing ligand pose prediction methods and ranking and scoring methods, and a Stage 2 subchallenge testing only ligand ranking and scoring methods after the release of all blinded co-crystal structures. Two smaller curated sets of 18 and 15 ligands were developed to test alchemical free energy methods. This overview summarizes all aspects of GC2, including the dataset details, challenge procedures, and participant results. We also consider implications for progress in the field, while highlighting methodological areas that merit continued development. Similar to GC2015, the outcome of GC2 underscores the pressing need for methods development in pose prediction, particularly for ligand scaffolds not currently represented in the Protein Data Bank (http://www.pdb.org), and in affinity ranking and scoring of bound ligands.
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D3R grand challenge 2015: Evaluation of protein–ligand pose and affinity predictions
Article
Full-text available
  • Sep 2016
  • J COMPUT AID MOL DES
The Drug Design Data Resource (D3R) ran Grand Challenge 2015 between September 2015 and February 2016. Two targets served as the framework to test community docking and scoring methods: (1) HSP90, donated by AbbVie and the Community Structure Activity Resource (CSAR), and (2) MAP4K4, donated by Genentech. The challenges for both target datasets were conducted in two stages, with the first stage testing pose predictions and the capacity to rank compounds by affinity with minimal structural data; and the second stage testing methods for ranking compounds with knowledge of at least a subset of the ligand–protein poses. An additional sub-challenge provided small groups of chemically similar HSP90 compounds amenable to alchemical calculations of relative binding free energy. Unlike previous blinded Challenges, we did not provide cognate receptors or receptors prepared with hydrogens and likewise did not require a specified crystal structure to be used for pose or affinity prediction in Stage 1. Given the freedom to select from over 200 crystal structures of HSP90 in the PDB, participants employed workflows that tested not only core docking and scoring technologies, but also methods for addressing water-mediated ligand–protein interactions, binding pocket flexibility, and the optimal selection of protein structures for use in docking calculations. Nearly 40 participating groups submitted over 350 prediction sets for Grand Challenge 2015. This overview describes the datasets and the organization of the challenge components, summarizes the results across all submitted predictions, and considers broad conclusions that may be drawn from this collaborative community endeavor.
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On the relationship between docking scores and protein conformational changes in HIV-1 protease
Article
  • Jun 2019
  • J MOL GRAPH MODEL
We present a detailed investigation of the effect of the crystallographic structure of the HIV-1 protease (PR) on the binding energy of different classes of inhibitors obtained from docking simulations. The crystal structures of 222 HIV-1 proteases (in wild-type and mutant forms) and 202 inhibitors were downloaded from appropriate databases. A cross-docking approach (docking of all 202 inhibitors to all 222 PR structures) using Autodock Vina was implemented. The protease structures were clustered using a Kohonen self-organization map analysis of the data matrix of docking energies. The obtained clusters of PRs were correlated with the x-y-z coordinates of the PR structures to identify structural segments underlying this clustering. The PR structures were clustered into 4 classes. One of these classes exhibits rather strong binding with almost all inhibitors, while another class exhibits rather weak binding. The remaining two classes are intermediate in binding strength. The selectivity ratio indices for the carbon-alpha atoms of the PR structures indicate that conformational motion of residues outside the binding pocket contributes significantly to the discrimination of the 4 classes.
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Novel and efficient synthesis of triazolobenzodiazepine analogues through the sequential Ugi 4CR-click-N-arylation reactions
Article
  • Feb 2019
  • TETRAHEDRON LETT
An efficient approach for the synthesis of N-alkyl-2-aryl-2-(6-oxo-4H-benzo[f][1,2,3]triazolo[1,5-a][1,4]diazepin-5(6H)-yl)acetamides is described. The protocol involves Ugi four-component reaction of 2-bromobenzoic acid, propargylamine, aldehydes and isocyanides followed by in situ sequential click reaction of azide ion with triple bond and N-arylation reaction to afford desired products in good to excellent yields.
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Novel family of fused tricyclic [1,4]diazepines: Design, synthesis, crystal structures and molecular docking studies
Article
  • May 2017
  • TETRAHEDRON
An efficient one-pot strategy for the synthesis of a new family of imidazo[1,4]diazepines has been developed and its mechanism has been proposed, which follows a seven-membered ring closure reaction. The condensation of 2- and 4-imidazolecarboxaldehyde with pyrazole amines provides six compounds 1–6, which are based on two types of fused tricyclic scaffolds. All presented compounds were fully spectroscopically characterized and their structure was unambiguously determined by single crystal X-ray crystallography. Molecular docking studies reveal a high similarity between binding modes of diazepines 1, 6 and eticlopride in the dopamine D3 receptor, as well as between enantiomers 2S, 6S and nortriptyline in dopamine transporter DAT.
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Dopamine Reuptake Inhibitors in Parkinson's Disease: A Review of Nonhuman Primate Studies and Clinical Trials
Article
  • Apr 2016
  • J PHARMACOL EXP THER
Striatal dopamine deficiency is the core feature of the pathology of Parkinson's disease (PD), and dopamine replacement with l-3,4-dihydroxyphenylalanine (l-DOPA) is the mainstay of PD treatment. Unfortunately, chronic l-DOPA administration is marred by the emergence of dyskinesia and wearing-off. Alternatives to l-DOPA for alleviation of parkinsonism are of interest, although none can match the efficacy of l-DOPA to date. Catechol-O-methyltransferase and monoamine oxidase inhibitors are currently used to alleviate wearing-off, but they do not increase "on-time" without exacerbating dyskinesia. Alternate approaches to dopamine replacement in parkinsonism generally (and to wearing-off and dyskinesia, specifically) are therefore urgently needed. Inasmuch as they increase synaptic dopamine levels, dopamine transporter (DAT) inhibitors, whether they are selective or have actions on noradrenaline or serotonin transporters, theoretically represent an attractive way to alleviate parkinsonism per se and potentially enhance l-DOPA antiparkinsonian action (provided that sufficient dopamine terminals remain within the striatum). Several nonhuman primate studies and clinical trials have been performed to evaluate the potential of DAT inhibitors for PD. In this article, we review nonhuman primate studies and clinical trials, we summarize the current knowledge of DAT inhibitors in PD, and we propose a hypothesis as to how tailoring the selectivity of DAT inhibitors might maximize the benefits of DAT inhibition in PD.
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ChemInform Abstract: Recyclable Gallium(III) Triflate-Catalyzed [4 + 3] Cycloaddition for Synthesis of 2,4-Disubstituted-3H-benzo[b][1,4]diazepines.
Article
  • Mar 2014
  • ChemInform
The Ga(OTf)3-catalyzed cyclocondensation of o-phenylenediamines with internal aroyl phenyl alkynes is developed resulting in generally good yields of benzodiazepines.
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Software News and Update AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.
Article
  • Jan 2010
AutoDock Vina, a new program for molecular docking and virtual screening, is presented. AutoDock Vina achieves an approximately two orders of magnitude speed-up compared with the molecular docking software previously developed in our lab (AutoDock 4), while also significantly improving the accuracy of the binding mode predictions, judging by our tests on the training set used in AutoDock 4 development. Further speed-up is achieved from parallelism, by using multithreading on multicore machines. AutoDock Vina automatically calculates the grid maps and clusters the results in a way transparent to the user.
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