Computational Drug Repurposing Approach

to Identify Potential Fatty Acid-Binding Protein-4

Inhibitors to Develop Novel Antiobesity Therapy

Somdutt Mujwar and Vivek Kumar various cancers, including breast, ovary, prostate, liver, and so
on.1–5 Body mass index (BMI) is a measure to classify obesity
Institute of Pharmaceutical Research, GLA University, and overweight, it is weight of person (in kg) divided by square
Downloaded by Cornell University package NERL from www.liebertpub.com at 08/21/20. For personal use only.

Mathura, India. of height (in meters)- kg/m2. According to WHO, BMI ‡25 is
overweight and BMI ‡30 is considered as obesity. In 2016,
greater than 1.9 billion adults (18 years or more) were over-
ABSTRACT
weight and out of them 650 million were obese.
Obesity is a chronic human disorder caused by multiple factors,
Worldwide, about 13% of the world population were found
causing excessive accumulation of fat because of the disparity in
to be obese, out of which 11% were men and 15% were
take of energy intake with respect to its expenditure. Genetic,
women. It was estimated that about 41 million children
environmental, and behavioral factors are having a crucial role in
around the globe who are younger than the age of 5 years are
its pathogenesis. Fatty acid-binding protein (FABP) is a super-
suffering from obesity.5 According to NCD Risk Factor Col-
family that was involved in the transportation, metabolism, and
laboration in between 1975 and 2014, there was a surge in the
storage of lipids. The experimental studies have revealed that
prevalence of obesity from 3.2%–10.8% in adult men and
there is a significant rise in the fatty acid-binding protein-4
6.4%–14.9% in women.6 According to the major health sur-
(FABP4) expression, and plasma concentration in obese and its
vey of the nation—National Family Health Survey India-3
downregulation or inhibition can be a potential drug target for
(NFHS-3), 9% of men (15–49 years) and 13% of women (15–
obesity. Repurposing of drugs is a trending method for the
49 years) were found to be obese or overweight in 2005–06.
identification of the newer pharmacological action of an es-
In this study, in silico approaches have been used to design
tablished drug molecule having initially approved indication. It is
or identify the potential lead molecules against a specific drug
a cost-effective and economical approach for the development
target.7 This process utilizes the fast computation to perform
of alternative therapies for existing dreadful diseases in quick
docking simulation at the molecular level. The binding af-
succession. Thus, the in silico drug repurposing technique is a
finity of ligand against the specific drug target can be deter-
highly effective approach for identifying an existing drug mol-
mined by simulating the environmental conditions same as
ecule having an antiobesity therapeutic activity against the
present in the body. This technique is very much fast and
human FABP4, and Floxacillin was selected as safe and effective
requires fewer manpower as well compared to other tech-
drug for candidates for developing an antiobesity therapy.
niques.8,9 The novel biological roles of preexisting and ap-
proved drugs can be identified through drug repurposing,
Keywords: drug repurposing, drug repositioning, fatty
which is a cost-effective approach and establish an alterna-
acid-binding protein, obesity
tive therapy for existing diseases. It provides rational and
systemic solution for recognizing treatment options compared
INTRODUCTION to conventional drugs.8,10

O
besity and overweight are characterized as un-
natural and extravagant deposition of lipids to an
extent that it adversely affects the health, becoming
the major risk factor for lethal ailments such as
cardiovascular disease (heart attack, stroke, hypertension, cor-
onary artery disease, and atherosclerosis), diabetes type II, os-
teoarthritis, liver and gall bladder disease, hyperlipidemia, and
The abnormal accumulation of fat in obese is a consequence
of dysfunctional adipocytes, which are further marked by
hypertrophy, changes in cellular composition, intensification
of lipid storage, dysfunction in sensitivity to insulin, and re-
lease of proinflammatory mediators.11 Fatty acid-binding
proteins (FABP) are a superfamily that was involved in the
transportation of lipids, till date nine members have been

DOI: 10.1089/adt.2020.976 ª MARY ANN LIEBERT, INC.  VOL. XX NO. XX  XXXX 2020 ASSAY and Drug Development Technologies 1
 MUJWAR AND KUMAR
identified from FABP. They have an affinity for long-chain
fatty acids and others, and are mostly found in the tissues that
are involved in the metabolism or the storage of lipids.12
Adipocyte FABP (A-FABP/aP2/FABP-4) is mostly present in
the mature adipocytes, adipose tissues, and macrophages.
Peroxisome proliferator-activated receptor-g agonist, insulin,
fatty acids, and dexamethasone regulate the expression of
fatty acid-binding protein-4 (FABP4).13,14 The animal studies
have shown that there is a significant rise in the FABP4 ex-
pression and plasma concentration in obese and its down-
regulation or inhibition can be a potential drug target for
obesity, atherosclerosis, diabetes mellitus, and insulin resis-
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tance.15,16 In cross-sectional studies, it has been shown that
FABP4 is closely linked with obesity and metabolic syndrome
and can be used in their prophylaxis.17,18
Drug repurposing, is a trending method for the identifi-
cation of the newer pharmacological action of an estab-
lished drug molecule having initial approved indication. It is
a cost-effective and economical approach for development
of alternative therapies for existing dreadful diseases in a
quick succession.19,20 The drug repurposing methods are
applied by using various in silico techniques like virtual
screening of libraries of approved drugs as well as molecular
docking simulation of a drug against a newer target.
Computer-assisted in silico approaches are used to analyze,
integrate, and apply large-scale information retrieved from
scientific reports.8,10
Thus, in the present study, the drug repurposing approach is
applied by virtually screening a ligand library containing
2,890 FDA-approved existing drugs for developing novel
therapies for obesity.
MATERIALS AND METHODS
The molecular docking simulation of FABP4 was performed
by performing underneath procedures.
Selection and Preparation of Protein
The three-dimensional (3D) structural model of human
FABP4 bound with ligand 2,4,6-triisopropylbenzoic acid
(76D) was procured from the Research Collaboratory for
Structural Bioinformatics (RCSB) protein data bank database
(pdb id-4NNT).21,22 The complexed ligand molecule 76D
within the active ligand-binding site of the receptor was
separated with the help of the software chimera (Resource for
Biocomputing, Visualization, and Informatics RBVI, USA).
The preparation of the receptor molecule for performing
docking simulation was done by deleting redundant water
molecules, addition of the polar hydrogen, and Gasteiger
charge with its equal distribution among residues.
2 ASSAY and Drug Development Technologies XXXX 2020
Ligand Preparation
Ligand 76D was prepared for performing docking simula-
tion by assigning the number of nonrotatable, rotatable, and
unrotatable bonds within the ligand 76D and it was saved
in *.pdbqt format by AutoDock software (The Scripps Research
Institute, USA).23
Docking Simulation
Molecular docking is an artificial intelligence-based
method to predict the preferred orientation of a ligand toward
a specific macromolecule to form a complex based on their
biomolecular interactions. The observed interactions between
the two can be further utilized to calculate the binding energy
to identify the strength of association between them.
The active ligand-binding site was identified in the FABP4
by exploring its binding interactions through Discovery Stu-
dio Visualizer software (Accelrys, Inc., BIOVIA, USA). The
binding site of the FABP4 was utilized to itemize the size and
position of the grid-box for performing the docking simula-
tion. The grid-box was placed by centering the ligand to cover
its each and every extended conformation as well as the
binding residues.
A docking parameter file was prepared to perform the
docking simulations for each of the ligand. The docking pa-
rameters used in the current computational study includes 150
Genetic Algorithm (GA) runs, 250,000 maximum numbers of
evaluations, 27,000 maximum numbers of generations, and
0.02% rate of gene mutation. All the above-stated docking
parameters are saved in a file known as docking parameter
file.23,24
The AutoDock utilizes semiempirical or hybrid force field
by considering the principles of both molecular as well as
quantum mechanics. The binding free energy of a specific
ligand against a target macromolecule is calculated as
DG = DH - TDS,
where the DH represents the enthalpic and TDS the entropic
contribution.
The negative DG value represents the favorable binding as
the enthalpic term decreases because of the favorable inter-
molecular interactions and formation of intermolecular
bonds, whereas the entropic term tends to increase due to, for
example, loss of degrees of freedom.
Validation of the Docking Parameters
The potential binding modes of the bound inhibitor mole-
cule were represented by their docked position and orienta-
tions. The different parameters considered to perform docking
simulation were validated by redocking the crystallized 76D
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 DRUG REPURPOSING FOR NOVEL ANTIOBESITY THERAPY

ligand against the FABP4.24 Following parameters were used
to validate the docking process of the FABP4 against its
known inhibitor ligand 76D.
The scoring function in the AutoDock is evaluated by
considering the experimentally observed protein-ligand
complex as a positive control and the root mean square de-
viation (RMSD) of the other docked ligands can be considered
with respect to this bound ligand.
The RMSD compares the average distance between atoms of
two ligands through the following equation:
sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
1 n  2
+ ðaix - bix Þ2 + aiy - biy + ðaiz - biz Þ2 ,
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ecule was further saved in pdbqt format by AutoDock. The
processed macromolecular structure has been represented in
Figure 1.
Ligand’s Preparation for Docking
All the four bonds present in the ligand molecule were kept
rotatable in the current experimental study. The 3D structure
of 76D ligand is shown in Figure 2. The processed ligand
molecule was also saved in the pdbqt format for performing
docking simulation by using AutoDock software.
Binding-Site Identification and Formation of Grid-Box

RMSD(a, b) =
n i=1
where a*i* refers to the atoms of molecule 1, and b*i* to
the atoms of molecule 2, respectively. The subscripts x, y, and
z are denoting the x–y–z coordinates for every atom.
Overlay methods. The docking simulation was validated only
when the ligand’s docked conformation was flawlessly over-
laid with its bioactive crystallized conformation.
The bound ligand 76D is having major interactions with the
ARG126, SER53, and PHE16 amino acids within the active
ligand-binding site of FABP4. An imaginary 3D grid-box was
prepared by wrapping all the macromolecular binding resi-
dues interacting with the ligand. The grid-box is shown in the
Figure 3 and their coordinates are tabulated in Table 1.

Chemical resemblance. Also, the docked ligand should have

similar chemical interactions with the target macromolecule
as those were present in the bioactive crystallized macromo-
lecular complex.

In Silico Virtual Screening of the FDA-Approved

Existing Drugs
The ligand library consisting of 2,890 FDA-approved drugs
obtained from the ZINC database was virtually screened
against the human FABP4 for exploring potential lead mol-
ecules. The lead molecules are expected to be potential in-
hibitors of human FABP4.25

Comparative Study with Existing FABP4 Inhibitors

The shortlisted molecules on the basis of best binding en-
ergy observed against FABP4 receptor in virtual screening
were comparatively studied by performing the molecular
docking with the existing reported FABP4 inhibitors. Some of
the 2,4,6-triisopropylbenzene-derived potent FABP4 inhibi-
tors reported by Cai et al. were used to perform internal val-
idation of the newly identified FABP4 inhibitors through
virtual screening.26
Fig. 1. Crystal structure of the human FABP4: the 3D structural
RESULTS model of human FABP4 procured from the RCSB database protein
Selection and Preparation of Protein data bank (PDB ID-4NNT) and processed for docking simulation by
The 4NNT protein complex of human FABP4 procured from the addition of polar hydrogens, Gasteiger charge, and removal of
redundant water molecules by AutoDock software. 3D, three-
the RCSB database protein data bank consist a single poly- dimensional; FABP4, fatty acid-binding protein-4; RCSB, Research
peptide chain of 152 amino acids. The processed macromol- Collaboratory for Structural Bioinformatics.

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 MUJWAR AND KUMAR

Table 1. The Grid Coordinates for the Human Fatty

Acid-Binding Protein-4
Spacing
Proteins x - D y - D z - D (Á) x Center y Center z Center
4NNT 40 40 40 0.375 -4.044 6.823 -19.784

Docking Parameters
The docking parameter file consisting of various docking
parameters for the present studies was utilized by AutoDock
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software for performing docking simulation of the 76D ligand

against the prepared human FABP4. The results obtained after
docking study of the bound ligand 76D with the FABP4 are
shown in Table 2. The 3D binding confirmation ligand 76D is
shown in Figure 4.

Docking Method Validation

Fig. 2. Bound ligand 76D separated from human FABP4: The The molecular docking simulation of 76D against the
bound ligand 76D was alienated from the macromolecular FABP4 FABP4 was successfully validated by following parameters.
complex by Chimera software. 76D, 2,4,6-triisopropylbenzoic acid.

Overlay methods. The docked conformation of the ligand 76D

was perfectly overlaid over the bioactive conformation of
the ligand present in the receptor complex obtained from the
RCSB protein data bank with a RMSD value of 1.01. The
perfect overlapping of the docked conformation of 76D with
respect to its crystallized conformation successfully validates
the molecular docking simulation process and parameters
utilized for performing the same. The overlaid conformation
of the docked ligand with reference to the bioactive crystal
structure of the ligand obtained from RSCB protein data bank
is shown in Figure 5.

Chemical resemblance. The docked ligand 76D is having the

similar binding interactions that were present in the bioactive
conformation obtained from the crystallized enzyme com-
plex. The interactions present in the crystal structure and the
docked structure are shown in Figure 6.

Table 2. Docking Results of 76D Ligand Against the Fatty

Acid-Binding Protein-4
Interacting Binding energy Binding
Proteins Ligand residues RMSD (Kcal/Mol) affinity (lM)
4NNT 76D Arg126, Ser53 1.01 -6.80 10.36
and Phe16
Fig. 3. 3D grid box for molecular docking simulation of human
FABP4: A 3D imaginary grid-box wrapping all the active ligand- 76D, 2,4,6-triisopropylbenzoic acid; RMSD, root mean square deviation.
binding residues present in the receptor molecule.

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Fig. 4. 3D docked conformation of 76D: the docked conformation of 76D in the active binding cavity of human FABP4 obtained by using
PyMOL software.

Virtual Screening of the Drug Library

Out of ligand library containing 2,890 FDA-approved
drugs, drug molecules having potential binding affinity for
the human FABP4 were selected on the basis of the lowest
binding energy in the predefined range of -5 to -15 kcal/mol.
The binding energy obtained for top 15 drug molecules after
performing molecular docking simulation-based virtual
screening is given in Table 3.
The two-dimensional and 3D interaction of top three lead
molecules, that is, Medroxyprogesterone, Drospirenone, and
Floxacillin are shown in Figures 7–9.

Comparative Study with Existing FABP4 Inhibitors

The internal validation of the screened FABP4 inhibitors in
the current study was successfully achieved by screening the
existing reported FABP4 inhibitors against the target macro-
molecule.26 The results obtained in the internal validation of
the newly identified FABP4 inhibitors are demonstrated in
Table 4.

Fig. 5. Overlay conformation of the docked ligand: the superim-
position of the docked conformation of the ligand with reference to
its bioactive conformation of the ligand present in the crystallized
structure of the target protein.
DISCUSSION
Discovery of some selective and diverse drug targets in-
volved in the metabolism of lipids are highly beneficial to
develop newer clinically active antiobesity drugs. The

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Fig. 6. Binding mode and chemical interactions of the bound ligand 76D: The binding interactions of the docked conformation as well as
the bioactive conformation are procured by using the software DS Visualizer.

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 DRUG REPURPOSING FOR NOVEL ANTIOBESITY THERAPY

Table 3. The Binding Energy of the Top 10 Drug Molecules existing drug is identified and established through computa-
Obtained After AutoDock Based Virtual Screening tional and clinical investigations. Drug repurposing and re-
of Ligand Library Containing 2,890 FDA-Approved Drugs positioning techniques are widely applied in the modern era for
Binding the successful development of newer therapy for the diseased
S. no. Name Structure energy Name condition via existing drugs. In the earlier days, the newer
pharmacological role of an existing drug was identified by
1 ZINC05763835 -9.79 Medroxyprogesterone
its accidental use or either observed by their clinical mani-
festations. Nowadays fast, economical, reliable, and versatile
2 ZINC03927200 -9.52 Drospirenone computational repurposing techniques were utilized to rec-
ognize a newer functional role of an existing drug molecule.
3 ZINC04102187 -9.44 Floxacillin
Drug repurposing is a trending approach, which is nowadays
used for the identification of a novel pharmacological action of an
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existing drug molecule.10,25 In this context, in silico drug re-

purposing approach is utilized in the current biochemical stand-
4 ZINC03978006 -9.41 Dicloxacillin
point to develop a novel therapy targeting the human FABP4.
In the current biochemical standpoint, the 3D structure model
of human FABP4 complexed with ligand 76D is obtained from
5 ZINC03875334 -9.32 Cortisone the RCSB protein data bank. The bound ligand 76D is separated
from the complex enzyme with the help of chimera software. The
separated ligand molecule is docked in the active binding site of
6 ZINC03876078 -9.27 Estradiol
the target protein by using AutoDock software for validating the
7 ZINC04213057 -9.19 Dromostanolone parameters utilized in the molecular docking process. Further-
Propionate more, the target protein is screened with a ligand library con-
sisting of 2,890 FDA-approved drug molecules to identify
8 ZINC13298436 -9.15 Irbesartan
potential FABP4 inhibitors to develop novel antiobesity therapy.
The results obtained by performing molecular docking
simulation-based virtual screening was successfully validated
as all the reported inhibitors were showing the binding energy
in the predefined inhibitory range, but none of the existing
9 ZINC03876186 -9.12 Estrone sulfate FABP4 inhibitor has shown higher binding energy value than
the identified inhibitors in the current in silico study.
10 ZINC29051126 -9.12 Retapamulin The findings of the current in silico virtual screening methods
lead to identification of molecules like Medroxyprogesterone,
Drospirenone, Floxacillin, Dicloxacillin, Cortisone, Estradiol,
Dromostanolone Propionate, Irbesartan, Estrone sulfate, Re-
tapamulin, and so on as potential FABP4 inhibitors.
collection of clinically approved drugs would be highly Medroxyprogesterone is a progesterone derivative used to
valuable for developing novel antiobesity therapy to counter treat conditions such as absent or irregular menstrual periods,
the obesity affecting mankind. or abnormal uterine bleeding. The Medroxyprogesterone
The drug development process is a very complex process, binds in the active binding cavity of human FABP4 by mainly
which requires about 15–20 years as well as 2–3 billion US interacting with ARG106, MET20, TYR128, ARG126, PHE16,
dollars for discovery of a new chemical entity. To overcome the CYS117, ALA75, and TYR19 residues. Drospirenone is a syn-
high cost and time required for developing a drug molecule, in thetic progesterone derivative, which is used in birth control
silico drug repurposing and repositioning techniques are pills to prevent pregnancy and in menopausal hormone therapy.
promising alternative methods. In the current paradigm of ARG106, PHE16, CYS117, ALA75, and TYR19 of human FABP4
conventional drug discovery process, the drug repurposing are found to be interacting with the Drospirenone. Floxacillin is
approach reveals an alternative economical and time saving a narrow-spectrum b-lactam antibiotic of the penicillin class.
substitute having a higher success rate. Drug repurposing is a Floxacillin is found to be interacting with the ARG106, MET20,
technique, in which a newer pharmacological application of an ARG78, PHE16, ARG126, CYS117, and ALA75 residues of the

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Fig. 7. 2D and 3D binding interactions of Medroxyprogesterone: The binding interactions of Medroxyprogesterone with the human FABP4.
2D, two-dimensional.

Fig. 8. 2D and 3D binding interactions of Drospirenone: The binding interactions of Drospirenone with the human FABP4.

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Fig. 9. 2D and 3D binding interactions of Floxacillin: The binding interactions of Floxacillin with the human FABP4.

Table 4. The Binding Energy Obtained in Virtual Screening of the Previously Reported Fatty Acid-Binding
Protein-4 Inhibitors
S. no. Code Name Structure Binding energy
1 2a 2-methyl-1-(2,4,6-triisopropylphenylsulfonyl)-1-H-benzoimidazole -8.97

2 4d 5-chloro-2-methyl-1-(2,4,6-triisopropylphenylsulfonyl)-1-H-benzoimidazole -8.78

3 m1 1-(2,4,6-triisopropylphenyl- sulfonyl)-1-H-imidazole -7.79

4 10 2,4,6-triisopropylbenzoic acid -6.85

5 8 2,4,6-triisopropylbenzenesulfon- amide -6.69

6 LA Linoleic Acid -4.34

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 MUJWAR AND KUMAR
human FABP4. Dicloxacillin is a narrow-spectrum b-lactam
antibiotic of the penicillin class. It is used to treat infections
caused by susceptible gram-positive bacteria.
The structure activity relationship of the shortlisted lead
molecules revealed on the basis of the in silico binding pattern
with the human FABP4 clearly suggests that the residues like
ARG106, PHE16, CYS117, and ALA75 plays an important role in
the binding of the drug molecule with the drug target. The re-
purposing techniques are highly promising for reproducing the
new biological role of existing drugs. The identified bioactive
molecules may be useful for developing novel therapies against
the obesity in the near future. These drugs should be further
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explored through preclinical and clinical studies for validating
the proposed hypothesis in the current biochemical standpoint.27
CONCLUSION
In silico drug repurposing technique is a highly effective ap-
proach for identifying an existing drug molecule having an an-
tiobesity therapeutic activity against the human FABP4. A ligand
library containing 2,890 drug molecules approved by the FDA
was virtually screened against the human FABP4. It was observed
that Medroxyprogesterone, Drospirenone, Floxacillin, Diclox-
acillin, Cortisone, Estradiol, Dromostanolone Propionate, Irbe-
sartan, Estrone sulfate, Retapamulin, Spironolactone, and so on
were potential lead molecules against human FABP4. The mole-
cules established for neurological, hormonal, as well as anticancer
therapy are supposed to interfere with the healthy individuals and
results in the undesirable side effects. Based on their safety profile,
Floxacillin was selected as safe and effective drug candidates
for developing an antiobesity therapy against human FABP4.
ACKNOWLEDGMENT
The authors are thankful to the IPR, GLA University, Mathura,
for providing all the necessary facilities to complete the work.
DISCLOSURE STATEMENT
No competing financial interests exist.
FUNDING INFORMATION
The author(s) received no specific funding for this work.
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Address correspondence to: Abbreviations Used

Somdutt Mujwar, PhD 2D ¼
two-dimensional
Institute of Pharmaceutical Research 3D ¼
three-dimensional
GLA University 76D ¼
2,4,6-triisopropylbenzoic acid
A-FABP/aP2/FABP-4 ¼
Adipocyte FABP
Mathura FABP ¼
fatty acid-binding protein
Uttar Pradesh 281406 FABP4 ¼
fatty acid-binding protein-4
India RCSB ¼
Research Collaboratory for Structural
Bioinformatics
E-mail: somduttmujwar@gmail.com RMSD ¼ root mean square deviation
Downloaded by Cornell University package NERL from www.liebertpub.com at 08/21/20. For personal use only.

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