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Surega and Vadivelu, IJPSR, 2023; Vol. 14(9): 4611-4621.
E-ISSN: 0975-8232; P-ISSN: 2320-5148
IJPSR (2023), Volume 14, Issue 9 (Research Article)
Received on 31 January 2023; received in revised form, 24 March 2023; accepted 26 April 2023; published 01 September 2023
STRUCTURE-BASED VIRTUAL SCREENING AND IDENTIFICATION OF POTENTIAL

INHIBITORS OF MYCOLIC ACID BIOSYNTHESIS ENZYMES (KASA, INHA, PKS13) FOR
THE TREATMENT OF TUBERCULOSIS
A. Surega and Annapoorna Vadivelu *
Department of Pharmaceutical Chemistry, College of Pharmacy, Mother Theresa Post Graduate and
Research Institute of Health Sciences, Gorimedu - 605006, Puducherry, India.
Keywords: ABSTRACT: Tuberculosis (TB) is caused by a bacterium
Mycolic acid, Molecular docking, β- called Mycobacterium tuberculosis, identified as a global health emergency
keto acyl ACP synthase, Enoyl acyl by the world health organization. The development of drug-resistance stains
ACP-reductase and Polyketide due to spontaneous gene mutation has been a major boost to research in the
synthase 13 pathogenicity and biochemistry of Mtb. To combat drug resistance to
Correspondence to Author: tuberculosis, new drugs and methodologies are emerging. Since, starting
Dr. Annapoorna Vadivelu itself mycobacterium complex cell wall has been a choice for widely selected
Associate Professor, targets for anti-TB drugs. Peptidoglycan, arabinogalactan, and mycolic acid
Department of Pharmaceutical are the basic layers supporting cell growth. The current work investigates
Chemistry, College of Pharmacy, virtual screening for optimal small molecule inhibitors targeted against
Mother Theresa Post Graduate and selected mycolic acid targets (β-keto acyl ACP synthase, enoyl acyl ACP-
Research Institute of Health Sciences, reductase and Polyketide synthase 13). A small library of 485 compounds
Gorimedu - 605006, Puducherry, was designed and docked into a selected target core to identify the potential
India. inhibitor. The designed compounds were subjected to docking studies using
Glide (Schrodinger). InhA was the most suitable mycolic acid inhibitor target
E-mail: cvapoorna@gmail.com
for the designed compounds. Further, the effectiveness of the study was
evaluated by comparing the docking score of known molecules against
selected targets with the designed library.
INTRODUCTION: Mycobacterium tuberculosis A six-month course of conventional therapy using
is the bacteria that causes tuberculosis (TB). four anti-microbial medications, including
Although TB germs typically assault the lungs, isoniazid, rifampin, ethambutol, and pyrazinamide,
they can also affect the kidney, spine, and brain. is used to treat the condition. This regimen does not
One-third of the world's population is infected by encourage patient compliance 1. Antimicrobial
tuberculosis (TB), which claimed 10.4 million new resistance occurs when the bacteria become
cases and 1.8 million fatalities in 2015. Depending resistant to the drugs, and the same way the TB
on the person, the chance of developing the active bacteria becomes resistant to the drug.
illness may change and rise in the presence of risk
factors like HIV or other co-infections. Various drug-resistant TB occurs, and they are
multi-drug resistant, pre-extensively drug-resistant
QUICK RESPONSE CODE TB, and extensively drug-resistant TB. The present
DOI:
10.13040/IJPSR.0975-8232.14(9).4611-21 study shows various mode behind the
antitubercular activity of the designed hetero
moiety derived from both naturally isolated
This article can be accessed online on
www.ijpsr.com phytoconstituents and chemical entities like furan,
semicarbazides, phenylhydrazine, pyrimidine,
DOI link: http://doi.org/10.13040/IJPSR.0975-8232.14(9).4611-21 chalconeand Guanidine 2–5.
International Journal of Pharmaceutical Sciences and Research 4611

Surega and Vadivelu, IJPSR, 2023; Vol. 14(9): 4611-4621. E-ISSN: 0975-8232; P-ISSN: 2320-5148
The cell wall of mycobacterium tuberculosis Researchers have studied the mechanism of the
consists of 3 layers, outer layer (mycolic acid), selected enzyme for over a decade and their
middle layer (arabinogalactan polysaccharide) and inhibition proves their role in the antitubercular
the inner layer (peptidoglycan). The hydrophobic activity 10.
nature of the complex cell wall acts as a barrier for
many compounds. In the present study, mycolic One of the key enzymes involved in the FAS-II
acid constituting the outer layer of the cell wall, has system's biosynthetic pathway is KasA. KasA is the
been selected as a target 6. key enzyme involved in the FAS-II system's
biosynthetic pathway. The acyl carrier protein
Mycolic acids are distinctive fatty acids found in (acpM), the ketoacyl-ACP synthases kasA and
the lipid-rich cell wall of Mycobacterium kasB, ketoreductase (mabA) and the enoyl
tuberculosis. These long-chain fatty acids, mostly reductase are all encoded by one operon in the
found covalently connected to the peptidoglycan- FAS-II complex. KasA catalyzes a condensation
arabinogalactan complex of the mycobacterial cell reaction that accepts the AcpM-bound acyl chain
wall, have an alkyl side chain and a hydroxyl group from InhA and elongates the acyl chain by two
at the and α and β positions. In addition, mycolic carbon atoms. The depletion of KasA gives rise to
acids can be found as free mycolic acids or as cell lysis and eventually leads to cell death. Thus,
elements of the lipids that make up the outer cell this enzyme has been considered an attractive drug
envelope. 'Housekeeping' fatty acids, necessary for target for treating tuberculosis 11–12.
biological processes like cell membrane
production, are where mycolic acids are produced One of the enzymes from the FAS-II system in M.
from 7. tuberculosis is the enoyl-acyl carrier protein
reductase, InhA. It is an NADH-dependent, enoyl-
Mycolic acids have a variety of significant acyl carrier protein reductase and is the target of
properties, including resistance to chemical isoniazid, a prodrug used in the first-line treatment
damage, resistance to dehydration, and, most of tuberculosis. To inhibit InhA activity, isoniazid
significantly, their limited permeability, which must be activated by KatG, a catalase-peroxidase
supports the pathogen's inherent therapeutic enzyme. Once activated, isoniazid turns into an
resistance. As a result, it has become clear that the unstable species that reacts with the NADH
enzymes involved in the biosynthesis of mycolic cofactor bound to the InhA active site, forming a
acids provide good targets for the invention of new covalent adduct. Until today, both INH and ETH
anti-mycobacterial agents 8, 9. are prodrugs available. They are activated by either
KatG or EthA enzyme, respectively, generating a
reactive oxygen species (ROS) that ultimately
impairs InhA and disrupt mycolic acid chain
elongation 13, 14.
Polyketide synthase 13 (Pks13) is an essential
enzyme in the synthesis of mycolic acids in Mtb.
This enzyme catalyzes a Claisen-type condensation
reaction between two long-chain fatty acyls
(meromycolyl-AMP and carboxyl-acyl-CoA) to
produce α-alkyl-β-ketoacyl derivatives, the
precursors of mycolic acids.
FIG. 1: ENZYMATIC PATHWAY OF MYCOLIC ACID
BIOSYNTHESIS Polyketide synthase (PkS13) is a multifunctional
protein critical in the polyketide biosynthetic
Among the various targets available in the mycolic pathway. Pks13 inhibition blocks the synthesis of
acid pathway, Fig. 1 three enzymatic targets kasA mycolic acids; therefore, Pks13 is a promising
(β-ketoacyl acyl carrier protein (ACP) synthase A), target for antituberculosis drug development 15, 16.
InhA (Enoyl-acyl carrier ACP reductase) and Pks The course of the study and research has been
13 (Polyketide synthase 13) were selected.

identifying a new molecule for antitubercular targets involved in the mycolic acid pathway. The
prophylaxis capable of inhibiting drug-resistant work layout is shown in Fig. 2.
FIG. 2: PLAN OF WORK
MATERIALS AND METHODS 17: 5V40). Using the protein preparation wizard of the
Docking Study: Molecular docking was performed Maestro molecular modeling interface, these
by using Maestro (13.3) molecular modelling protein structures were further refined for the
interface (Schrodinger. Inc., New York, USA) docking study (Schrodinger). Hydrogen atoms were
against the selected mycolic acid macromolecule. added after bond orders were determined. Utilizing
the OPLS3e force field, the produced protein
Antitubercular Library Preparation: A set of structures energy was minimized. The "Glide's
485 molecules was designed from a detailed Receptor Grid Generation" tool was used to create
literature survey to find effective inhibitors against receptor grid boxes at the active site residues which
three major drug targets of the mycolic acid are responsible for the antitubercular activity.
pathway in Mtb. All these compounds were
prepared using the Ligprep module for geometry Structure-Based Virtual Screening: The
optimization and energy minimization using compounds were eliminated using a structure-based
Schrodinger software for docking study with virtual screening technique based on docking score.
selected targets of mycolic acid pathway β-ketoacyl The results of a molecular docking study are used
acyl carrier protein (ACP) synthase A(KasA), to determine the interactions between the important
Enoyl-acyl carrier ACP reductase (InhA), amino acid residues in the protein and
Polyketide synthase (PkS). the molecules with low-energy conformations.
Protein Preparation and Grid Generation: The Studies of molecular docking were performed using
three mycolic acid targets are selected from the GLIDE (Grid-based Ligand Docking with
RCSB PDB databank (www.rcsb.org) based on the Energies). The target enzymes active sites were
X-ray diffraction crystallography and good maintained rigid during docking by GLIDE, while
resolution factor having PDB ID; KasA (PDB ID: ligands were allowed to move.
4C73), InhA (PDB ID: 2X23), Pks13 (PDB ID:

FIG. 3: CORE STRUCTURAL FRAGMENTS OF DESIGNED LIGANDS
All the 485, compounds in the dataset were docking protocol. XP docking gave us a good
subjected to the structure-based virtual screening correlation between pose and score, but the free
using HTVS (High-throughput virtual screening), binding energy of the ligand-receptor complex was
SP (standard precision), XP (Extra precision) responsible for the potential therapeutic action.
S. no. R1 R1 R2 R3
1 1-(furan-2-yl)ethan-1-one Bis[4-(dimethylamino) phenyl] Benzaldehyde Thiosemicarbazide
methanone
2 1-phenylpropan-1-one Cyclobutyl (phenyl) methanone Furaldehyde Semicarbazide
3 1-phenylpentan-1-one Cyclopropyl(4-methoxyphenyl) Cinnamaldehyde Amino guanidine
methanone
4 1-(4-methoxyphenyl)ethan-1- (1-methylcyclohexyl) (phenyl) Vanillin Phenyl hydrazine
one methanone
5 1-(4-methylphenyl) ethan-1-one Phenyl (pyridin-2-yl) methanone Salicyaldehyde Guanidine
hydrochloride
6 (3Z)-4-phenylbut-3-en-2-one 2,2,2-trifluoro-1-phenylethan-1-one
7 4-(4-methoxyphenyl)butan-2- 5-methyloctan-3-one
one
8 1-cyclopropylethan-1-one (4-aminophenyl) (phenyl)
methanone
9 1,2-diphenyl ethan-1-one 9H-xanthen-9-one
10 4-methylpentan-2-one N,N'-diphenylurea
TABLE 1: DOCKING SCORE OF THE DESIGNED LIGANDS AGAINST SELECTED TARGETS USING HTVS
MODE
S. no. Binding Affinity Range No. of Compounds Scored Against Different Targets
KasA InhA PkS
1 -9.1 to -10 0 1 0
2 -8.1 to -9 22 60 11
3 -7.1 to -8 112 116 109
4 -6.1 to -7 132 134 161
5 -5.1 to -6 116 112 105
6 -4.1 to -5 73 72 44

7 -3.1 to -4 37 41 16
8 -2.1 to -3 12 11 6
9 -1.1 to -2 2 10 2
10 -0.1 to -1 0 1 0
The best score of approximately 100 compounds is selected compounds were docked by XP mode and
selected and it is allowed to dock under standard the best 10 compounds with high binding affinity
precision (SP) mode and the various binding are mentioned for 3 targets.
conformations of compounds are studied. The
TABLE 2: DOCKING SCORE (KCAL/MOL) OF COMPOUNDS AGAINST Β-KETO ACYL ACP SYNTHASE (KASA)
S. NO. Compound G Score Dock Score Lipophilic Score H Bond Score
1 A248 -10.07 -10.07 -6.13 -0.36
2 A364 -9.12 -9.12 -4.52 -2
3 A447 -9.00 -9.00 -7.44 -0.7
4 A208 -8.88 -8.88 -6.11 -0.07
5 A434 -8.78 -8.78 -7.15 -0.48
6 A270 -8.77 -8.77 -6.21 -0.54
7 A267 -8.62 -8.62 -5.66 -1.16
8 A188 -8.49 -8.49 -5.83 -0.16
9 A276 -8.45 -8.45 -5.32 -0.46
10 A196 -8.44 -8.44 -5.05 -0.37
TABLE 3: DOCKING SCORE (KCAL/MOL) OF COMPOUNDS AGAINST ENOYL ACYL ACP-REDUCTASE (INHA)
S. no. Compounds G Score Dock Score Lipophilic Score H Bond Score
1 A434 -11.73 -11.73 -7.34 -1.64
2 A237 -11.74 -11.66 -6.26 -1.62
3 A189 -11.61 -11.53 -5.85 -0.48
4 A294 -11.27 -11.27 -5.58 -1.72
5 A281 -11.24 -11.24 -5.05 -1.81
6 A448 -10.84 -10.84 -6.23 -1.19
7 A34 -10.82 -10.82 -5.75 -1.18
8 A282 -10.79 -10.79 -5.65 -1.62
9 A342 -10.70 -10.69 -5.85 -0.87
10 A402 -10.63 -10.63 -6.82 -0.61
TABLE 4: DOCKING SCORE (KCAL/MOL) OF COMPOUNDS AGAINST POLYKETIDE SYNTHASE 13 (PKS13)

S. no. Compounds G Score Dock Score Lipophilic Score H Bond Score
1 A245 -10.87 -10.871 -7.16 -2.06
2 A202 -10.15 -10.159 -6.49 -2.14
3 A188 -9.455 -9.455 -6.92 -1.03
4 A248 -9.454 -9.454 -4.36 -4.00
5 A180 -9.22 -9.228 -6.66 -1.07
6 A185 -8.96 -8.963 -6.50 -0.96
7 A184 -8.74 -8.747 -6.31 -1.18
8 A242 -8.71 -8.714 -4.42 -2.04
9 A336 -8.55 -8.551 -5.81 -1.14
10 A233 -8.52 -8.523 -5.78 -1.91
TABLE 5: HYDROGEN BONDING INTERACTIONS, DISTANCE AND INTERACTING AMINO ACID RESIDUES
OF STUDIED MACROMOLECULES WITH SELECTED LIGANDS
KasA
Compounds Interacting residue No. of H bonds Distance
A248 Gly200, H2O molecule 2 1.86, 1.92
A364 Glu199 1 2.58
A447 Pro201 1 2.75
A208 Gly200 1 2.06
InhA
A434 Ile194 1 3.53

A237 Lys165 4 1.96; 2.85

H2O molecule 3.47; 2.69
A294 Ile194 1 4.05
A281 Ile194 1 3.55
Pks13
A245 Gln1633, H2O molecule, Hie1664 3 2.84, 2.58, 2.49
A202 Gln1633 2 1.73,1.73
A188 H2O molecule, Gln1633 3 2.79, 2.36 1.96
A248 H2O molecule, Hie 1664, Gln 1633, 6 2.06, 2.75,2.55, 1.93,
Ser 1636 2.01, 1.77
A180 H2O molecule 1 2.41
RESULTS AND DISCUSSION: The present docked on KasA under HTVS mode in the range (-
study showed the mycolic acid inhibitory activity 1 to -9). A248 interacted with gly 200 and water
of the docked molecule was evaluated through a molecules by forming 2 hydrogen bonds Fig. 4.
molecular docking study using glide. The A364 interacted with glu199 by forming 1
compounds’ structures were drawn using Marvin hydrogen bond Fig. 5.
sketch, and the energy minimization was done.
A447 interacted with pro201 by forming 1
All the designed compounds show different glide hydrogen bond Fig. 6. A208 interacted with gly200
score, coulomb energy, and Vander Waal’s energy by forming 1 hydrogen bond Fig. 7. A434
due to difference in structural features. The docking interacting residue was not identified. Different
study showed that most of the compounds formed a binding interactions are shown in Table 4.
hydrogen bond with KasA. All the compounds
FIG. 4: INTERACTION AND HYDROGEN BOND DETAILS OF COMPOUND A248 WITH KASA

The compound A248 shows the best inhibitory A237 interacted with lys165 and H2O molecule by
activity to KasA with a glide energy of -48.978, forming 4 hydrogen bonds Fig. 9. A294 interacted
Vander Waal’s energy of -44.060 and coulomb with ile194 by forming 1 hydrogen bond Fig. 10.
energy of -4.918. A281 interacted with ile194 Fig. 11.
The docking study showed that most of the Binding interactions are shown in the table. The
compounds formed a hydrogen bond with InhA. compound A434 shows as the best compound to
All the compounds docked on InhA under HTVS InhA, glide energy is -44.784, Vander Waal’s
mode in the range (-0.1 to -10). A434 interacted energy is -43.551 and coulomb energy is -1.232.
with ile194 by forming 1 hydrogen bond Fig. 8.
FIG. 8: INTERACTION AND HYDROGEN BOND DETAILS OF COMPOUND A434 WITH INHA

The docking study showed that most compounds A202 interacted with gln1633 by forming 2
had a binding affinity with Pks13. All the hydrogen bonds Fig. 13. A188 interacted with
compounds docked on Pks under HTVS mode gln1633 and H2O by forming 3 hydrogen bond Fig.
showed dock score in the range (-1 to -9). A245 14. A248 interacted with ile194 by forming 6
showed the highest glide score with a glide energy hydrogen bonds Fig. 15. A180 interacted with
of -61.095, Vander Waal’s energy of -47.994 and water molecules by forming 1 hydrogen bond Fig.
coulomb energy of -13.101. A245 showed 16. Different binding interactions are shown in
interaction with gln1633, H2o molecule and Table 4.
Hie1644 by forming 3 hydrogen bonds Fig. 12.

FIG. 12: INTERACTION AND HYDROGEN BOND DETAILS OF COMPOUND A245 WITH PKS13

CONCLUSION: From the given study, we can affinity are the following: (a) more than 2 nitrogen
identify which selected macromolecule might be and oxygen donors, (b) the presence of unsaturation
responsible for the antitubercular activity and the (c) the presence of oxygen and nitrogen (acceptor)
details of the lead molecule could be figured out. alongside carbon might increase electron density in
Since almost all the designed ligands have good the region and d) more than two aryl groups All of
Glidescore against InhA, it can be stipulated as the these characteristics encourage H-bonding with the
most suitable macromolecule through which InhA active site, resulting in a high Glide score.
compounds drawn showed their antitubercular The absence of any of the above structural features
mechanism. In contrast, compounds A34, A35, leads to decreased binding score cum interaction
A37, A43, A434, A237, A245, A189, A195, A294 and affinity of the compounds with the target
and A281 showed the best glide score for InhA macromolecule.
macromolecule. Glide score is related to ligand
effectiveness to a macromolecular target. ACKNOWLEDGEMENT: The authors thank the
HOD and Department of Pharmaceutical Chemistry
The best Glide score, maximum H-bonds, and staff. The authors also thank Schrodinger. Inc.,
potential Van der Waals and coulomb energies New York, USA for providing the software.
between the ligand and receptor were determined
by docking results for the compounds A184, A237, CONFLICTS: Nil
A245, and A294, which might be regarded as a
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How to cite this article:
Surega A and Vadivelu A: Structure based virtual screening and identification of potential inhibitors of mycolic acid biosynthesis enzymes (KasA,
inhA, Pks13) for treatment of tuberculosis. Int J Pharm Sci & Res 2023; 14(9): 4611-21. doi: 10.13040/IJPSR.0975-8232.14(9).4611-21.
All © 2023 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
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Surega and Vadivelu, IJPSR, 2023; Vol. 14(9): 4611-4621.

E-ISSN: 0975-8232; P-ISSN: 2320-5148

IJPSR (2023), Volume 14, Issue 9 (Research Article)

STRUCTURE-BASED VIRTUAL SCREENING AND IDENTIFICATION OF POTENTIAL

International Journal of Pharmaceutical Sciences and Research 4611

International Journal of Pharmaceutical Sciences and Research 4612

FIG. 2: PLAN OF WORK

International Journal of Pharmaceutical Sciences and Research 4613

FIG. 3: CORE STRUCTURAL FRAGMENTS OF DESIGNED LIGANDS

International Journal of Pharmaceutical Sciences and Research 4614

TABLE 4: DOCKING SCORE (KCAL/MOL) OF COMPOUNDS AGAINST POLYKETIDE SYNTHASE 13 (PKS13)

International Journal of Pharmaceutical Sciences and Research 4615

A237 Lys165 4 1.96; 2.85

International Journal of Pharmaceutical Sciences and Research 4616

International Journal of Pharmaceutical Sciences and Research 4617

International Journal of Pharmaceutical Sciences and Research 4618

International Journal of Pharmaceutical Sciences and Research 4619

International Journal of Pharmaceutical Sciences and Research 4620

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