Chemistry Research Journal, 2017, 2(1):42-45

Available online www.chemrj.org

ISSN: 2455-8990
Research Article CODEN(USA): CRJHA5

In silico Pharmacokinetic and Toxicity study of Some Selected Antidepressant Drugs

Shashank Shekhar Mishra*1, Chandra Shekhar Sharma1, Hamendra Pratap Singh1, Neeraj
Kumar2, Harshda Pandiya3
1
Department of Pharmaceutical Chemistry, Bhupal Nobles’ College of Pharmacy, Udaipur 313001, India
2
Department of Pharmaceutical Chemistry, Geetanjali Institute of Pharmacy, Udaipur 313001, India
3
Bhupal Nobles’ College of Pharmacy, Udaipur 313001, India

Abstract Major depressive disorders affect the general health and reduce the life quality. The treatments approaches
are used to treat major depressive disorders are counselling and antidepressant medication. Due to occurrence of
serious but low adverse events, there is essential need to design and develop new drug with lesser toxic and higher
potency. In this work, we performed the evaluation of pharmacokinetic descriptors, bioactivity score and various
types of toxicities through computational methods.

Keywords Anxiety, Drug-likeness, Nuclear receptor ligands, Teratogenicity

Introduction
Major depressive disorders also known as depression is characterized by dysthymia, anxiety and low mood state at
least two weeks. This depressive disorder negatively affects the general health as well as person’s personal work,
school life. Major people who die by suicide had depression or other mood disorders [1]. 253 million people are
affected from major depressive disorder according to global burden of disease study 2013 [2]. The chances of
depressive condition are enhanced with neurological diseases such as stroke, psychosis and parkinson’s disease. The
interesting fact about this major depressive disorder is it found more in urban areas as compared to rural areas [3].
The pathophysiology of depression is not clearly understood but the cause of depression includes the genetic,
environmental and mostly psychological factors. The treatments approaches are used to treat major depressive
disorders are counselling and antidepressant medication. In comparison with counselling approach, antidepressant
medication appears to be more effective but causes serious adverse events. So, it is quite essential to make new
potent antidepressant agents which have lesser adverse events with higher antidepressant activity.

Materials and Methods

In silico ADME analysis
There are various physicochemical features and pharmacokinetic descriptors were calculated for some selected
antidepressant agents through the online tool Molinspiration Cheminformatics server
(http://www.molinspiration.com). Molinspiration Cheminformatics offers broad range of tools supporting molecule
manipulation and processing, including SMILES and SDfile conversion, normalization of molecules, generation of
tautomers, molecule fragmentation, calculation of various molecular properties needed in quantitative structure
activity relationship (QSAR) study, molecular modeling and drug design, high quality molecule depiction,
molecular database tools supporting substructure and similarity searches. This software also provides fragment-

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based virtual screening, bioactivity prediction and data visualization. Molinspiration tools are written in Java,
therefore can be used practically on any computer platform [4]. Drug-likeness is qualitative concept used for drug
like property that described as a complex balance of various molecular properties and structural features which
determine whether particular molecule is similar to the known drugs. These molecular properties are mainly
hydrophobicity, electronic distribution, hydrogen bonding characteristics, molecule size and flexibility and of course
presence of various pharmacophoric features that influence the behaviour of molecule in a living organism,
including bioavailability, transport properties, affinity to proteins, reactivity, toxicity, metabolic stability and many
others. Drug-likeness evaluated by the Lipinski rule of five that deals four simple physicochemical parameter ranges
(MWT ≤ 500, log P ≤ 5, Hbond donors ≤ 5, H-bond acceptors ≤ 10) associated with 90% of orally active drugs that
have passed phase II clinical status [5]. Other calculation methods such as ligand efficiency and lipophilic efficiency
can also be used to express drug-likeness as parameters of potency.

In silico Bioactivity analysis

The bioactivity score of selected agents were also evaluated using the tool Molinspiration Cheminformatics server
(http://www.molinspiration.com). In this computational chemistry technique large chemical databases are analyzed
in order to identify possible new drug candidates.
In the Molinspiration tool, the miscreen engine first analyze a training set of active structures (in extreme case even
single active molecule is sufficient to built a usable model) and compares it with inactive molecules by using
sophisticated Bayesian statistics. Only SMILES or SD file structures of active molecules are sufficient for the
training, no information about the active site or binding mode is necessary. This is particularly useful in projects
where structure-based approach cannot be applied because information about 3D receptor structure is not available,
for example in screens aiming to find ligands modulating G-protein coupled receptors. Based on this analysis a
fragment-based model is developed, where for each substructure fragment a bioactivity contribution is calculated.
Once a model is build the bioactivity of screened molecules may be then calculated as a sum of activity
contributions of fragments in these molecules. This provides a molecule activity score (a number, typically between
-3 and 3). Molecules with the highest activity score have the highest probability to be active. Such in silico screening
is very fast, large collections of molecules (more than 100'000 molecules) may be screened in an hour.
Based on the protocol described above, screening models developed for four important drug classes, namely GPCR
ligands, ion channel blockers, kinase inhibitors, and nuclear receptor ligands. A virtual screening model for any
target may be developed easily by using the miscreen built-in functionality. Another advantage of virtual screening
protocol based on Bayesian statistics is, that it is able to generalize, i.e. to learn general structure requirements which
are necessary for bioactivity. The identified new bioactive molecules are therefore not limited to molecules similar
to the training set, but the protocol is able also to identify new active structure classes (scaffold hopping).

In silico Toxicity analysis

The toxicity of the selected antidepressant agents was evaluated by computational method using Pallas version 3.1
ADMETox prediction software pentium IV processor. This software tool was started by double click on the icon.
The molecule to be predicted was drawn by double click on new option, and then molecule was subjected for
evaluation of toxicity by selecting ToxAlert options.

Result and Discussion

There some antidepressant agents were selected and analyzed to pharmacokinetic properties and drug likeness
(Lipinski’s rule of five) which are given in Table 1. All selected agents have molecular weight in the acceptable
range (MWT ≤ 500). Low molecular weight containing molecules are easily absorbed, diffused and transported as
compared to high molecular weight compounds. As molecular weight increases except certain limit, the bulkiness of
the molecules are also increases comparably [6].

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Table 1: ADME Properties of Antidepressant agents

Name Molecular Molecular LogP TPSA nON nOHNH nrotb volume In silico %
formula weight absorption
Isocarboxazide C12H13N3O2 231.25 1.23 67.16 5 2 4 210.01 85.82
Phenelzine C8H12N2 136.20 0.45 38.05 2 3 3 141.34 95.87
Pargyline C11H13N 159.23 1.90 3.24 1 0 3 169.25 107.88
Imipramine C19H24N2 280.42 4.16 6.48 2 0 4 287.31 106.76
Doxepine C19H21NO 279.38 3.85 12.47 2 0 3 277.32 104.69
Bupropion C13H18ClNO 239.75 3.42 29.10 2 1 4 228.54 98.96
Fluoxetine C17H18NOF 309.33 4.53 21.26 2 1 7 275.13 101.66
Sertraline C17H17Cl2N 306.24 3.98 12.03 1 1 2 267.90 104.84

Among selected antidepressant agents, all are found to be within acceptable range. The MLogP (octanol / water
partition co efficient) of all agents were calculated and found to be within acceptable range according to Lipinski’s
rule. The MLogP value is used to calculate the lipophilic efficiency that measures the potency of drug. Therefore
Octanol-water partition coefficient logP value is essential in rational drug design and QSAR studies. In the
pharmacokinetic study, hydrophobicity of the molecule is assessed by evaluating logP value because hydrophobicity
plays a vital role in the distribution of the drug in the body after absorption [7]. TPSA (Topological Polar Surface
Area) is a very useful physiochemical parameter of molecule that gives the information about polarity of
compounds. This parameter was evaluated for analyzing drug transport properties. Polar surface area is the sum of
all polar atoms mainly oxygen and nitrogen including attached hydrogen [8]. Percent absorption were also evaluated
for all selected antiepileptic agents by %ABS = 109- (0.345 * TPSA) [9]. Molecular volume assesses the transport
properties of the molecule such as blood-brain barrier penetration. The number of rotatable bond was calculated and
have found relevant. A molecule which have more number of rotatable bond become more flexible and have good
binding affinity with binding pocket.
Bioactivity of all selected antimalarial agents was evaluated against six different protein structures. Biological
activity is measured by bioactivity score that are categorized under three different ranges-
1. If bioactivity score is more than 0.00, having considerable biological activity.
2. If bioactivity score is 0.5 to 0.00, having moderately activity.
3. If bioactivity score is less than -0.50, having inactivity [10].
The result of this study was found that the selected agents are biologically active and have physiological effect. The
bioactivity score profile of the all selected agents is given in Table 2.
Imipramine, Doxepine, Fluoxetine and Sertraline having good bioactivity score against GPCR ligand which could
indicates they could bind more effectively with GPCR.
The bioactivity score provide the information about the binding cascade of the drugs that is used for the
development of a new functional drug with increased binding selectivity profile and less undesirable effects.
Table 2: Bioactivity of Antidepressant agents
Name GPCR Ion channel Kinase Nuclear receptor Protease Enzyme
Ligand modulator inhibitor ligand inhibitor inhibitor
Isocarboxazide -0.46 -0.63 -0.74 -1.10 -0.60 -0.41
Phenelzine -1.14 -1.07 -1.32 -1.81 -0.94 -0.40
Pargyline -0.44 -0.21 -0.78 -0.98 -0.63 -0.09
Imipramine 0.25 0.16 0.10 0.00 -0.08 0.13
Doxepine 0.70 0.34 0.08 0.58 0.11 0.65
Bupropion -0.29 0.04 -0.86 -0.61 -0.19 -0.28
Fluoxetine 0.38 0.04 0.13 0.37 0.18 0.19
Sertraline 0.23 0.27 -0.37 -0.16 -0.12 0.02

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All selected antidepressant agents were evaluated to toxicity profile and given in Table 3. All of the drugs were
found to be highly probable to toxicity except sertraline, doxepine and pargyline.
These research findings provide the lead for the design and development of new potent antimalarial drugs.
Computational study of all selected antimalarial drugs gives the information about the pharmacokinetics of the
existing drugs that provide the lead for development of functional drug with more effectiveness and lesser toxicity.
Table 3: Toxicity Profile of Antidepressant agents

Immunotoxicity
Overall toxicity

Teratogenicity

Neurotoxicity
Mutagenicity
Oncogenicity

Sensitivity
Irritation
Name Toxicity

Isocarboxazide Highly Probable 72 72 67 29 53 0 0 29

Phenelzine Highly Probable 72 72 67 29 47 0 0 0
Pargyline Not Probable 0 0 0 0 0 0 0 0
Imipramine Highly Probable 71 0 71 0 0 0 0 0
Doxepine Not Probable 0 0 0 0 0 0 0 0
Bupropion Highly Probable 76 76 0 18 0 0 0 0
Fluoxetine Highly Probable 71 0 71 0 0 0 0 0
Sertraline Not Probable 42 40 42 38 0 0 29 40

References
1. Becker, S. J., Sanchez, C. C., Curry, J. F., & Tonev, S. S. S. (2008). Cognitive-behavioral therapy for
adolescent depression: processes of cognitive change. Psychiatric Times, 25(14), 46-46.
2. Lynch, V. A., & Duval, J. B. (2010). Forensic nursing science. Elsevier Health Sciences.
3. Flannelly, K. J., Galek, K., Ellison, C. G., & Koenig, H. G. (2010). Beliefs about god, psychiatric
symptoms, and evolutionary psychiatry. Journal of Religion and Health, 49(2), 246-261.
4. Sharma, C. S., Mishra, S. S., Singh, H. P., Kumar, N. (2016). In silico ADME and Toxicity Study of Some
Selected Antineoplastic Drugs. International Journal of Pharmaceutical Sciences and Drug Research, 8(1),
65-67.
5. Lipinski CA. Lead-and drug-like compounds: the rule-of-five revolution. Drug Discovery Today:
Technologies. 2004; 1(4):337-341.
6. Srimai V, Ramesh M, Parameshwar KS, Parthasarathy T. Computer-aided design of selective Cytochrome
P450 inhibitors and docking studies of alkyl resorcinol derivatives. Medicinal Chemistry Research. 2013;
22(11):5314-5323.
7. Abraham DJ. Burger's medicinal chemistry and drug discovery. Wiley Interscience, 2003.
8. Palm K, Stenberg P, Luthman, K, Artursson P. Polar molecular surface properties predict the intestinal
absorption of drugs in humans. Pharmaceutical research. 1997; 14(5):568-571.
9. Sharma CS, Verma T, Singh HP, Kumar N. Synthesis, characterization and preliminary anticonvulsant
evaluation of some flavanone incorporated semicarbazides. Medicinal Chemistry Research 2014;
23(11):4814-4824.
10. Verma A. Lead finding from Phyllanthus debelis with hepatoprotective potentials. Asian Pacific Journal of
Tropical Biomedicine. 2012; 2(3): S1735-S1737.

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