Molecular Docking and In Silico Cogitation
Validate Mefenamic Acid Prodrugs as Human
Cyclooxygenase-2 Inhibitor
Kamal Shah,1 Somdutt Mujwar,1 Jeetendra Kumar Gupta,1
Sushant K. Shrivastava,2 and Pradeep Mishra1
1
Department of Pharmaceutical Chemistry, Institute
of Pharmaceutical Research, GLA University, Mathura, India.
Downloaded by 193.56.66.162 from www.liebertpub.com at 09/29/19. For personal use only.
2
Department of Pharmaceutics, IIT BHU, Varanasi, India.
ABSTRACT
In silico molecular docking is an efficient technique for drug
design that predicts the optimized orientation of the ligand
against a specific drug target. This is a cost-effective and time-
saving technique that requires limited manpower. Nonsteroidal
anti-inflammatory drugs (NSAIDs) are commonly prescribed
drugs in various prescriptions. The drawbacks with NSAIDs in its
long-term usage are gastric irritation, bleeding, and perforation.
Prodrug approach is a commonly used method to overcome these
side effects. In this study, the reported prodrugs of mefenamic
acid were utilized to validate the molecular docking simulation
process by comparing obtained in silico results with the reported
in vivo results. The molecules were evaluated for their binding
affinity against human cyclooxygenase-2 enzyme as well as their
pharmacokinetics profile is predicted on the basis of Lipinski’s
and Veber rule. The in silico result showed high degree similarity
with experimental results. This confirms the efficiency and reli-
ability of the molecular docking technique for identification of
potential lead compounds.
Keywords: in silico, molecular modeling, mefenamic acid,
docking, Lipinski’s rule, NSAIDs
INTRODUCTION
N
onsteroidal anti-inflammatory drugs (NSAIDs) are
widely used for the treatment of pain, fever, and
inflammation from past so many years.1 Gastro-
intestinal (GI) irritation and ulcerogenicity occur
with prolong use of NSAIDs.2 Many researchers suggested
the divergent mechanism for the mucosal damage.3,4 These
are local annoyance produced by an acid group of the
NSAIDs as well as inhibition of prostaglandins in the GI
DOI: 10.1089/adt.2019.943 ª MARY ANN LIEBERT, INC.  VOL. 17 NO. 6  AUGUST/SEPTEMBER 2019 ASSAY and Drug Development Technologies
tract.5,6 The generation of reactive oxygen species is also a
significant cause of the formation of gastric mucosal lesions.
A possible way to solve this problem was derivatization of
the carboxylic functional group of NSAIDs into ester or
amide linked mutual prodrugs. So, to suppress the upper GI
irritation and bleeding, there is a need to design prodrugs of a
desired quality.7–10 In this study, an attempt has been made
to validate the molecules through docking simulation tech-
nique by comparing in silico results with the in vivo findings
of some reported prodrugs of NSAID category using mefe-
namic acid as decisive molecules.11–13 In silico approaches
have been used to design the potential lead molecules against
a specific drug target. It utilizes a fast computing technique
to perform docking simulation at the molecular level. The
outcome was used to predict the binding affinity of a ligand
against the target macromolecule by observing their ionic
and hydrophobic interactions between them through simu-
lating the environmental conditions present in our body.14
The in silico techniques for drug design are fast and
economical, as well as require very fewer manpower. The
work was also validated by this study that the experimen-
tally observed anti-inflammatory and analgesic activities of
these reported molecules were because of the inhibition of
cyclooxygenase-2 (COX-2) enzyme and not by any other
mechanism.11–13
MATERIALS AND METHODS (IN SILICO STUDY)
Selection of Macromolecule and Ligand Preparation
The human COX-2 bound with ligand mefenamic acid (pdb
id-5IKR) was downloaded from the protein data bank. The
receptor protein COX-2 was prepared for molecular docking
by removing ligand, and from the active site, removal of water
molecules that are not interacting with the ligand, and the
addition of polar hydrogens.15,16 The ligand mefenamic acid is
prepared for molecular docking simulation by providing the
rotatable, nonrotatable, as well as unrotatable bonds present
in the ligand through the AutoDock software.17 In this study,
four reported prodrugs of mefenamic acid, which had poten-
tial pharmacological activity against the human COX-2
285
 SHAH ET AL.
enzyme, were selected from the literature. These reported
drugs were utilized for in silico validation.
Identification of Binding Site
The ligand binding site of the human COX-2 protein is
identified by using protein visualization software such as DS
visualizer, PyMol, and chimera. The bound ligand mefenamic
acid was separated from the complex molecule by using
software chimera.18,19
Grid Box Formation and Maps Generation
The binding site of the COX-2 receptor is identified by using
various protein visualization software such as PyMol and DS
visualizer to enumerate the grid parameter points of the grid
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box required to perform the molecular docking simulation of
ligand molecules with the human COX-2 receptor. These grid
parameters were utilized for all docking runs. The grid box
was placed by centering the ligand molecule and covering all
the residues involved in the binding of the ligand. This ensures
that all the extended conformations of ligands fit within the
grid box. The separate map files for each of the atom types
present in the receptor as well as ligand, namely aromatic
carbon, carbon, hydrogen as electron donor, oxygen as elec-
tron acceptor, nitrogen, and sulfur as electron acceptor, are
prepared by running Autogrid utility of the AutoDock suite.
These map files prepared by Autogrid are used for carrying out
molecular docking simulations by AutoDock.
Docking Parameters
Lamarckian genetic algorithm (LGA) is one of the primary
conformational search approaches employed in AutoDock
for molecular docking simulation. A trail population is cre-
ated for various possible conformations. It is followed by
mutation, conformational parameter exchange, and compete
in a manner kindred to biological evolution in successive
generations for eventually selecting individuals with lowest
binding energy. The individual conformational search for its
local conformational space, discovering local minima and
then proceeding with this information to later generations, is
performed by ‘‘Lamarckian’’ aspect, which is its additional
feature. The binding energy of the small molecules with
macromolecular targets is predicted by using the semiem-
pirical force field. The force field allows the assimilation of
intramolecular energies into the predicted binding energy by
the evaluation of the energetics for both bound and unbound
states based on a comprehensive thermodynamic model.
Docking parameter file required for the docking of each
ligand molecule was prepared by using the 150 genetic al-
gorithm runs, 250,000 maximum number of evaluations,
286 ASSAY and Drug Development Technologies AUGUST/SEPTEMBER 2019
27,000 maximum number of generations, and 0.02% rate of
gene mutation.20
Docking Method Validation
The position and orientations of the ligand obtained af-
ter the molecular docking study represent probable binding
patterns of the inhibitors. The various docking parame-
ters considered in the docking methods were validated by
redocking individually crystallized ligand mefenamic acid over
COX-2 receptor. The molecular docking simulation technique
is validated by using the following parameters.
Binding energy. The molecular docking simulation method is
initially validated on the basis of the obtained binding energy.
The predefined range of binding energy should be in the range
from -5 to -15 kcal/mol.
Overlay methods. Further validation of the molecular docking
method is performed by the overlay method. The docked
conformation of the bound ligand should be impeccably
overlaid with reference to the bioactive conformation of the
ligand present in the crystal structure of the downloaded
protein.
Chemical resemblance. The molecular docking method is vali-
dated when the docked ligand should have the same interac-
tions with the residues of macromolecule as that present in the
downloaded crystallized macromolecule.
Molecular Docking Simulations and Result Analysis
The selected ligand molecules were docked against human
COX-2 enzyme by using in silico molecular docking simula-
tion technique to identify their affinity for the COX-2 enzyme.
The molecular docking simulation was performed by MGL
tools-based AutoDock software. MGL tools are a graphical
user interface for AutoDock-based molecular docking of li-
gand molecules against a macromolecule. The molecular
docking simulation process was validated at every step by
evaluating the input file name, coherent format of grid maps
and the existance of non-standard atom types. After per-
forming molecular docking simulation of the selected ligand
molecules against the human COX-2 enzyme, the best ligand
molecules were evaluated on the basis of their binding energy
against the COX-2 macromolecule. The LGA is used for
scoring. All the results obtained by molecular docking simu-
lation were evaluated on the basis of hydrophilic and lipo-
philic interactions obtained between the binding residues
present in the active ligand binding site of the macromolecule
and ligand. The empirical range of the free binding energy
ª MARY ANN LIEBERT, INC.
 IN SILICO VALIDATION OF MEFENAMIC ACID PRODRUGS
should be in the range. The mathematical equation to calcu-
late binding affinity of the specific ligand for a particular
target is as follows:
Ki = e[(DG=(RT)] ,
where DG is change in free energy upon binding, R is gas
constant, and T is temperature.
Absorption, Distribution, Metabolism,
Excretion, and Toxicity Prediction
The physicochemical parameters, as well as the toxicity
profile of all the selected ligand molecules, were evaluated by
using DataWarrior software. DataWarrior software checks
for the presence of major toxic effects such as mutagenic-
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ity, tumorigenecity, irritant effect, and reproductive effects
in the lead molecules. The DataWarrior software predicts
the presence of different types of toxic effects based on
the precomputed structural set of fragments responsible
for the toxicity of the specific ligand. These fragments were
generated by immense pulverizing Registry of Toxic Effects of
Chemical Substances database compounds responsible for
certain toxicity. This software searches for the presence of
those specific fragments that are responsible for the toxic
effects of ligand molecule. The DataWarrior program also
calculates drug likeness and drug score of the lead molecule
on the basis of their physicochemical properties.21,22
In Vivo Experimentation
The different derivatives of mefenamic acid were synthe-
sized. Steglich method of esterification was adopted for the
synthetic part. The final compounds synthesized were an ester
of mefenamic acid and paracetamol (MAP), ester of mefe-
namic acid and salicylamide (MAS), ester of mefenamic acid
and menthol (MAM), and ester of mefenamic acid and thymol
(MAT). The synthesized compounds were evaluated for the
anti-inflammatory activity and analgesic activities.
RESULTS
Selection of Macromolecule and Ligand Preparation
Human COX-2 bound to mefenamic acid (pdb id-5IKR) was
downloaded from the protein data bank database. The 5IKR
protein complex consists of two identical polypeptide chains
of 551 amino acids. Chain B was removed with the help of
chimera software and chain A was selected for the experiment.
The receptor molecule was prepared for the molecular docking
simulation process by adding polar hydrogen bonds, remov-
ing redundant water molecules, and the addition and distri-
bution of charge. After processing the receptor molecule, it
was saved in *.pdbqt format by using AutoDock software.
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Table 1. The Grid Coordinates for Human
Cyclooxygenase-2 Enzyme
Proteins x-D y-D z-D Spacing (Å) x center y center z center
5IKR 46 44 46 0.447 38.042 2.131 61.280
Three rotatable bonds were present in the ligand molecule. All
the three bonds were kept rotatable in the ligand molecule for
this study. The prepared ligand was saved in *.pdbqt format.
Identification of Binding Site and Grid Box Preparation
The amino acid residues TYR385 and SER530 were involved
in the active binding of the ligand mefenamic acid with the
human COX-2 enzyme. An appropriate grid box was prepared
by covering all the macromolecular residues that are involved
in the active binding of bound ligand mefenamic acid with the
human COX-2 receptor. The coordinates used for the prepa-
ration of the grid box are tabulated in Table 1.
Molecular Docking Simulations and Its Validation
The results obtained after molecular docking of the bound
ligand mefenamic acid with the human COX-2 receptor are
presented in Table 2. Molecular docking of a particular ligand
with a specific macromolecule was performed by considering
the following parameters.
Binding energy. Molecular docking simulation method was
validated as the binding energy of the bound ligand mefe-
namic acid with the human COX-2 receptor is -7.67 kcal/mol,
which lies in the predefined range of -5 to -15 kcal/mol.
Overlay method. The molecular docking method was validated
as the docked conformation of the ligand should be perfectly
overlaid with the crystal structure of the ligand present in the
downloaded protein with a significant root-mean-square
deviation (RMSD) value of 0.43. If the docked ligand
shows <2.0Å RMSD value with the crystallographic ligand,
it is considered as a successful docking.23,24 The overlaid
Table 2. Molecular Docking Results of Ligand Mefenamic
Acid with the Human Cyclooxygenase-2 Receptor
Internal Binding Binding
Interacting validation energy affinity
Protein residue RMSD (kcal/mol) (nM)
COX-2 TYR385 and SER530 0.43 -7.67 1321.7
COX-2, cyclooxygenase-2; RMSD, root-mean-square deviation.
ASSAY and Drug Development Technologies 287
 SHAH ET AL.
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Fig. 1. The superimposition of the docked conformation of the
ligand with reference to its bioactive conformation of the ligand
obtained from the crystal structure of the downloaded protein.
conformation of the docked ligand with reference to
the crystal structure of the downloaded ligand is shown in
Figure 1.
Chemical resemblance. The molecular docking method was
validated when the docked ligand had similar interactions
with the residues of macromolecule as that present in the
downloaded crystallized macromolecule. The interactions
present in the crystal structure are shown in Figure 2A and the
interactions present in the docked structure are shown in
Figure 2B.
Fig. 2. Binding mode and chemical interactions of the bound ligand mefenamic acid within the active ligand binding site of
cyclooxygenase-2 receptor of human.
288 ASSAY and Drug Development Technologies AUGUST/SEPTEMBER 2019
Molecular Docking Simulations
The binding affinity of all the ligand molecules was iden-
tified by analyzing the docked energy obtained for top rank-
ing pose of each ligand and interactions of docked compound
were visualized. The molecular docking results of all the four
molecules were obtained after performing AutoDock-based
molecular docking simulation against the human COX-2 re-
ceptor shown in Table 3.
Physicochemical Properties Evaluation
All the selected four ligand molecules were evaluated
for pharmacokinetics profiling by using DataWarrior pro-
gram and Marvin Sketch software. The physicochemical
properties of the lead molecules are selected on the basis
of Lipinski’s rule of five and Veber rule. The significant
physicochemical properties used in this study are calculated
partition coefficient, topological polar surface area, mo-
lecular weight, hydrogen bond donor, and hydrogen bond
acceptor sites. The physicochemical properties of all the four
ligand molecules for COX-2 enzyme protein of human are
given in Table 4.
Absorption, Distribution, Metabolism, Excretion,
and Toxicity Profiling of Lead Compounds
The physicochemical properties responsible for governing
pharmacokinetic profile of the drug molecule, such as ab-
sorption, distribution, metabolism, excretion (ADME), and
toxicity were evaluated by using DataWarrior software. The
following results were obtained. All the four ligand mole-
cules were tested for the presence of any major toxic effect
ª MARY ANN LIEBERT, INC.
 IN SILICO VALIDATION OF MEFENAMIC ACID PRODRUGS

Table 3. Binding Energy of All the Four Selected Ligand Molecules Against Human Cyclooxygenase-2 Enzyme
Binding energy Binding energy
S. No. Compound ID Chemical structure with COX-2 (kcal/mol) with COX-1 (kcal/mol)
1 Mefenamic acid -7.67 -7.25

HO HN
O
H3C CH3

2 MAP -8.77 -6.52

O HN
O
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H3C N H3C
H
CH3

3 MAS -8.60 -5.86

NH2
O O HN
O
H3C CH3

4 MAM -7.27 -5.99

O HN
O
H3C CH3

5 MAT -7.89 -5.96

O HN
O
H3C CH3

MAM, ester of mefenamic acid and menthol; MAP, ester of mefenamic acid and paracetamol; MAS, ester of mefenamic acid and salicylamide; MAT, ester of mefenamic
acid and thymol.

and it was observed that the reference molecule mefenamic
acid and molecule MAP were having an acceptable phar-
macokinetic profile with very good drug-likeness score, and
no or very low toxic effects. All the other ligand molecules,
that is, MAS, MAM, and MAT, were also found to have
an acceptable pharmacokinetics profile, but have low drug-
likeness score and some serious toxic effects such as mu-
tagenicity, tumorigenicity, and reproductive effects. The
ADME and toxicity results of all the selected ligand mole-
cules are given in Table 5.
DISCUSSION
The amino acids TYR385 and SER530 were active binding
residues present in the binding site for human COX-2. The
residues involved in the binding of the ligand mefenamic acid
were utilized for performing molecular docking simulation

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 SHAH ET AL.

Table 4. ‘‘Lipinski’s Rule of Five’’ for the Lead Molecules biologically active molecules was also validated by evaluat-
Targeting Cyclooxygenase-2 Enzyme ing their physicochemical parameters, which showed good
Drug
pharmacokinetic properties for reference ligand mefenamic
Compound ID Mol. Wt. ClogP TPSA (Å2) HBA HBD likeness acid and ligand MAP without the presence of any major toxic
effects.
Mefenamic acid 241.289 3.362 49.33 3 2 -0.897
The anti-inflammatory activity of these four ligands was
MAP 374.439 5.012 67.43 5 2 0.541 previously determined by Carrageenan paw edema model.
MAS 360.412 4.395 81.42 5 2 -0.098 This model validates that the drugs were exhibiting anti-
inflammatory activity. It may be due to simulation in mo-
MAM 379.542 6.557 38.33 3 1 -21.85
lecular docking. The results of in silico molecular docking
MAT 373.494 6.839 38.33 3 1 -0.898 studies clearly signify that the anti-inflammatory activity
ClogP, calculated partition coefficient; HBA, hydrogen bond acceptor; HBD, observed in these ligand molecules may be due to inhibition of
hydrogen bond donor; Mol. Wt., molecular weight; TPSA, two dimensional polar COX-2 enzyme. The binding affinity obtained after perform-
surface area. ing in silico molecular docking apparently anticipates with
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that of the percentage inhibition results achieved experi-

studies to analyze the binding affinity of the novel ligand
toward the receptor. Initially, the molecular docking simula-
tion process was validated by redocking of already bound
reference ligand on the basis of its binding energy and overlay
methods, which confirmed the similarity in binding patterns
obtained by molecular docking simulation studies with that
occurring inside the human body.
After successful validation of the molecular docking sim-
ulation technique, similar parameters were utilized to perform
molecular docking simulation-based screening by using se-
lected ligands. The results obtained in this study indicate that
AutoDock-based in silico screening successfully proves that
the anti-inflammatory activity of the reported ligand mole-
cules may be due to inhibition of the human COX-2 enzyme.25
A similar experimental study was also performed with COX-1
enzyme. The obtained in silico results given in Table 3 lie in
the predefined range of -5 to -15 kcal/mol, clearly indicating
the preferential COX-2 selectivity of the ligands. The binding
energy of all the studied ligands for the COX-2 enzyme was
having negative higher values, confirming the preferen-
tial COX-2 selectivity. The pharmacokinetic profile of the
Table 5. Toxicity Profiling of Cyclooxygenase-2 Inhibitor
Lead compound Mutagenic Tumorigenic
Mefenamic acid None None
MAP None None
MAS High Low
MAM None None
MAT None None
mentally. The ligand MAP shows leading binding affinity for
human COX-2 enzyme in in silico studies. The ligand MAP
implicated the best results in previously reported experi-
mental studies by imparting best anti-inflammatory activity
(% inhibition) among all the selected ligands. This signifies the
utility of in silico molecular docking technique to successfully
predict the pharmacological activity of the unknown ligand
molecules against specific targets. Similarly, the maximum
analgesic activity exhibited by MAP in previously reported
experimental data also strengthens the obtained in silico re-
sults. The predicted partition coefficient values of all the four
selected ligands also show only slight deviation of –0.3 from
experimentally determined values retrieved from the reported
literature. The in silico molecular docking simulation is a
structure-based technique used for the prediction of the
binding affinity of the unknown ligand molecules on the
basis of their chemical interaction with the target. Thus, the
in silico method can be relied upon for generation of the lead
compound.
CONCLUSION
AutoDock-based molecular docking simulation technique
is very useful in shortlisting potential lead compounds. The
four reported ligands MAP, MAS, MAM, and MAT were
studied against the human COX-2 enzyme. They exhibited
Irritant promising in silico results with potent inhibition of the COX-
High 2 enzyme by showing good binding affinity, good pharma-
cokinetic properties, and absence of any major toxic effects.
Low
The reported pharmacological activity of the selected four
Low ligand molecules showed reliable correlation with the
Low binding affinity obtained after performing in silico molec-
ular docking simulation against human COX-2 enzyme. The
Low physicochemical properties such as partition coefficient of
the ligands were predicted by using their two-dimensional

290 ASSAY and Drug Development Technologies AUGUST/SEPTEMBER 2019 ª MARY ANN LIEBERT, INC.
 IN SILICO VALIDATION OF MEFENAMIC ACID PRODRUGS

(2D) chemical structure. The observed deviation in the pre-
dicted value from the reported value may be due to the
difference in the three-dimensional conformational ar-
rangement of the ligands with respect to its 2D structural
arrangement in space. The obtained in silico results were
correlated with the reported experimental pharmacological
data to validate the authenticity of the in silico molecular
docking simulation technique.
ACKNOWLEDGMENT
The authors are thankful to the management of GLA Uni-
versity, Mathura, for providing all the necessary facilities to
complete this study.
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