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Docking Studies on Octa Peptides, Hexa Peptides Related to Human Histatin

and Apidaecin-IA and Dipeptide against DNA Gyrase and Sterol 14α-
Demethylase

Article · October 2014

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 RESEARCH ARTICLE

Docking Studies on Octa Peptides, Hexa Peptides Related to

Human Histatin and Apidaecin-IA and Dipeptide against DNA
Gyrase and Sterol 14α-Demethylase
Pandurangan Perumal1*, Vijay Prakash Pandey1
Abstract: Novel molecules can be used to treat the microbial infections including resistance microorganisms. DNA gyrase is an
essential enzyme belongs to a class of topisomerases IV which is essential for DNA synthesis leads to DNA transcription and
replication. Sterol 14α-demethylase is an enzyme that transferred the electrons from one molecule to another and catalyses the
oxidation or reduction reactions. The compounds AIA-II, AIA-I and DP-1 were showed potent against the DNA gyrase with glide
score -11.37, -8.94 and -8.53 as compared with standard amikacin, ciprofloxacin and streptomycin with glide score -13.88, -9.28
and -8.37. The compounds AIA-I and AIA-II were showed more potent against the sterol 14α-demethylase with glide score
11.13 and -10.07 as compared with standard amikacin and ciprofloxacin with glide score -9.87 and -5.85.

INTRODUCTION membrane proteins correlates with resistance to killing by

DNA gyrase is an essential enzyme belongs to a class of
topisomerases IV. [1-3] The topisomerase IV is essential for
DNA synthesis. DNA gyrase relaxes the positive supercoils
and catalyses the negative supercoils due to mechanical
stress leads to crossing of the two helices. It leads to DNA
transcription and replication. It is an intracellular target in
a number of antibacterial agents. Sterol 14α-demethylase is
an enzyme that transferred the electrons from one
molecule to another. [4] It catalyses oxidation or reduction
reactions. It is classified into 22 types. It acts as donors like
alcohol oxidoreductase, aldehyde or oxo group, amino acid
oxidoreducase, nitrogenous compounds, sulphur groups,
iron group, diphenols, hydrogen and oxygenases. It acts as
acceptor like superoxide radicals and peroxide or
peroxidises. Antimicrobial peptides (AMPs) are potent,
broad spectrum antibiotics which demonstrate potential as
novel therapeutic agents. [5-6] So for more than 850 AMPs
have been identified in various organisms from plants,
insects, animals and humans. [7-11] Characteristics of
bacteria that are resistant to antimicrobial peptides like
alteration of net surface charges: Staphylococcus aureus
transports D-alanine from the cytoplasm to the surface
teichoic acid to reduce the net negative charge by
introducing basic amino groups. S. aureus also modifies its
anionic membranes via Mprf with L-lysine, increasing the
positive net charge. Both of these mechanisms are likely to
repulse host defence peptides, which indicate a central role
for antimicrobial peptide resistance in the pathogenicity of
S. Aureus. Alterations in Lipid A: Salmonella species reduce
the fluidity of their outer membrane by increasing
hydrophobic interactions between an increased number of
Lipid A acyl tails by adding myristate to Lipid A with 2-
hydroxymyristate and forming hepta-acylated Lipid A by
adding palmitate. The increased hydrophobic moment is
thought to retard or abolish antimicrobial peptide insertion
and pore formation. Changes in membrane proteins: In
some gram-negative bacteria, for example Yersinia
enterocolitica, alteration in the production of outer
1Department of Pharmacy, Annamalai University, Annamalai Nagar,
Chidambaram-608002, Tamilnadu, India.
E-mail: perupharma78@gmail.com
*Corresponding author
antimicrobial peptides. Role of transporters: ATP binding
cassette transporters import antimicrobial peptides and
the resistance-nodulation cell-division efflux pump exports
antimicrobial peptides. Both transporters have been
associated with antimicrobial peptide resistance.
Proteolytic enzymes: Bacteria produce proteolytic
enzymes, which may degrade antimicrbial peptides leading
to their resistance. For example LL-37 is cleaved and
inactivated by an S. Aureus metalloproteinase named
aureolysin. The basic mechanism of the antimicrobial
peptides [12-14] such as 1) initial electrostatic and hydrogen
bond attraction; 2) subsequent hydrophobic interactions as
the peptides contact the target surface; 3) accumulation
and threshold concentration driving initial peptide
conformational dynamics and early membrane
deformation; 4) further peptide conformational phase
transition and insertion within the membrane core; 5) self-
association and multimerization; 6) formation of
quaternary peptide complexes such as barrel-stave or
toroid pore configurations; 7) translocation of peptide to
the inner facet of the cytoplasmic membrane; 8) ongoing
peptide accumulation and interactions and 9) access and
targeting of essential intracellular structures and functions.
METHODS
Protein Structure Preparation
The x-ray crystal structures of DNA gyrase (PDB: 3U2D)
and sterol 14α demethylase (PDB: 1E9X) retrieved from
the Research Collaboratory for Structural Bioinformatics
(RCSB) Protein Data Bank (Figure 1 and Figure 2) was used
in this study. Water molecules of crystallization were
detached from the composite and the protein was
optimized for docking using the protein preparation and
refinement utility provided by Schrödinger LLC. Partial
atomic charges were assigned according to the OPLS-AA
force field.
Ligand Structure Preparation
The ligand structures (Figure 3) were constructed using the
splinter dictionary of Maestro 9.3 (Schrodinger, LLC) using
the Optimized Potentials for Liquid Simulations-All Atom
(OPLS-AA) force field with the steepest descent followed by

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 RESEARCH ARTICLE

Figure 1: X-ray crystal structure of protein DNA gyrase (PDB: Figure 2: X-ray crystal structure of protein sterol 14α
3U2D) demethylase (PDB: 1E9X)
H2N
NH2+
NH2

NH2
HN
NH+
O
HN
H2N NH2
O
N O
H
NH
O NH2 O
O O O
N
H
DP-1 HN
N N
DP-2 O
H N
N NH2
NH2 N
H
O
O AIA-I

O H2N
O
NH2+
HN
NH2
N
H NH+
HN
O O HN
N
H3C H CH3 NH2

O CH3
O
DP-3 CH3
CH3
H2N NH2
O
O H HN N
N N H H
HN N
NH2 H
N
H CH3 O
O
O
H3C O O
N CH3 O
CH H CH
DP-4
H3C CH3 AIA-II

CH3 OH

NH+
HN
O

O OH
H2N O
NH2+ O O
H2N
H H
NH+ N N H
HN N N NH2
HN H N N N
H H H
O
O
O O O
O CH3
H CH3 CH3
N NH2
H HN N
N N H H NH2 HN HN
H N
O
O NH2
CH3 NH+ NH+
O
O
O

AIA-III
HH-I

H3C

NH2
NH2

H3C CH3
O NH2
NH2
O
O O
H2N
H H H3C CH3
N N H O
N N NH2 O
H N N N H O O
H H H N
H H
N N H
O N N NH2
O O O O
H N
H
N
H
N
H
CH3 O
H3C CH3 H3C O O O
CH3
H3C CH3 H3C
NH2
NH2 NH2
NH2
HH-II HH-III

Figure 3: Ligand structures

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 RESEARCH ARTICLE
Figure 4: Docking structure of compound AIA-I into the DNA Gyrase binding pocket
Figure 5: Docking structure of compound AIA-II into the DNA
gyrase binding pocket
curtailed Newton conjugate gradient protocol. Partial
atomic charges were computed using the OPLS-AA force
field.
Docking Protocol
All docking calculations were performed using the ‘‘Extra
Precision’’ (XP) mode of GLIDE program. The binding site,
for which the various energy grids were calculated and
stored, was defined in terms of two concentric cubes: the
bounding box, which must contain the center of any
acceptable ligand pose and the enclosing box, which must
contain all ligand atoms of an acceptable pose, with a root
mean square deviation (RMSD) of less than 0.5 Å and a
maximum atomic displacement of less than 1.3 Å were
eliminated as redundant in order to increase diversity in
the retained ligand poses. The scale factor for vander waals
radii was applied to those atoms with absolute partial
charges less than or equal to 0.15 (scale factor of 0.8) and
0.25 (scale factor of 1.0) electrons for ligand and protein,
respectively. The max keep variable which sets the
maximum number of poses generated during the initial
phase of the docking calculation were set to 5000 and the
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Figure 6: Docking structure of compound DP-I into the DNA
gyrase binding pocket
keep best variable which sets the number of poses per
ligand that enters the energy minimization was set to 1000.
Energy minimization protocol includes dielectric constant
of 4.0 and 1000 steps of conjugate gradient. Upon
completion of each docking calculation, at most 100 poses
per ligand were generated. The best docked structure was
chosen using a GLIDE score (Gscore) function. Another
scoring function used by GLIDE was E-model, which itself
derived from a combination of the Gscore, Columbic, van
der Waals and the strain energy of the ligand.
Qikprop Analysis
Qikprop efficiently evaluates pharmaceutically relevant
properties for over half a million compounds per hour,
making it an indispensable lead generation and lead
optimization tool. Accurate prediction of absorption,
distribution, metabolism, elimination (ADME) properties
prior to expensive experimental procedures, such as high
throughput screening (HTS), can eliminate unnecessary
testing on compounds that will ultimately fail; ADME
prediction can also be used to focus lead optimization efforts
to enhance the desired properties of a given compound.
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 RESEARCH ARTICLE
Figure 7: Docking structure of compound DP-3 into the DNA
gyrase binding pocket
Figure 9: Docking structure of compound AIA-I into the sterol
14α demethylase binding pocket
RESULTS
Qikprop Analysis
The ADME properties of the designed ligands were
predicted using Qikprop analysis. The compounds were
subjected to drug-likeness filter. All the designed ligands
were conformed and they were evaluated for docking using
GLIDE software.
Receptor Grid Generation
GLIDE receptor grid was generated to determine the size of
the active site. The most probable orientation of the ligands
in the binding pocket was identified and a scoring function
was used to quantify the strength of the interaction in a
molecule can make in a particular orientation. In order to
provide better correlation between good poses and good
scores, the GLIDE XP precision was favoured over the
standard mode.
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Figure 8: Docking structure of compound DP-4 into the DNA
gyrase binding pocket
Figure 10: Docking structure of compound AIA-II into the sterol
14α demethylase binding pocket
Validation of the Docking Protocol
The docking analysis was done for the ligands such with
the target protein DNA gyrase and sterol 14α demethylase
by using the docking software GLIDE and the docked
images are shown. The structures docked by GLIDE are
generally ranked according to the GLIDE Scoring Function
(more negative). The scoring function of GLIDE docking
program was presented in the G-score form. The most
straightforward method of evaluating the accuracy of a
docking procedure was to determine how closely the
lowest energy pose (binding conformation) predicted by
the object scoring function. In the present study, Extra
Precision GLIDE docking procedure was validated by
removing the inhibitor compound with DNA gyrase and
sterol 14 α-demethylase protein has been analyzed from
the G-score, GLIDE energy. To study the molecular basis of
interaction and affinity of binding of peptides to DNA
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 RESEARCH ARTICLE
Figure 11: Docking structure of compound DP-I into the sterol
14α-demethylase binding pocket
Figure 13: Docking structure of compound DP-3 into the sterol
14α-demethylase binding pocket
gyrase and sterol 14α-demethylase protein, all the ligands
were docked into the active site of DNA gyrase and sterol
14α-demethylase. The docking result of these ligands is
given in Table 1 and 2. The interaction energy includes van
der waals energy, electrostatic energy, as well as
intermolecular hydrogen bonding were calculated for each
minimized complex. The docking score using GLIDE varied
from -5.89 to -11.37 against DNA gyrase and -4.65 to -11.13
against sterol 14α demethylase. The GLIDE Score for the
standard amikacin, streptomycin, ciprofloxacin and
Isoniazid docked with DNA gyrase was -13.38, -9.28, -8.37
and -4.19. The GLIDE Score for the standard amikacin and
ciprofloxacin docked with sterol 14α demethylase was -
9.87 and -5.45. The GLIDE score can be used as a semi-
quantitative descriptor for the ability of ligands to bind to a
specific conformation of the protein receptor. AIA-II was
found more potent inhibition with -11.37 and DP-1, AIA-I
and DP-3 were showed the best inhibition against DNA
Gyrase with -8.53, -8.94 and 8.02 glidescore as compared
with standard. The compound AIA-I, AIA-II was found most
potent inhibition than standard against sterol 14α
demethylase with -11.13, 10.07 and HH-I were showed
potent inhibition against sterol 14α-demethylase with -
7.49. The compound DP-II and DP-IV were showed the
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[E-ISSN 2250-0308, P-ISSN 2249-359X]
Figure 12: Docking structure of compound DP-2 into the sterol
14α-demethylase binding pocket
Figure 14: Docking structure of compound DP-4 into the sterol
14α-demethylase binding pocket
significant inhibition against sterol 14α demethylase with -
8.09 and -6.25 glide score. The compound DP-2, DP-4 were
showed significant inhibition against DNA gyrase with -
6.05 and -5.89. The compound DP-3 and DP-1 showed
significant inhibition against sterol 14α demethylase with
6.28 and -4.65 glide score. We found a very good
conformity between the localization of the inhibitor and
crystal structure of the protein. The conformational
analysis of different docked complexes shows the
residues of ASP57, ASN54, GLU50, GLU58 and ASP81in
AIA-II of DNA Gyrase plays important role in this
receptor’s activity. The conformational analysis of
different docked complexes shows the residues of ALA73
and ASP67 in AIA-I and ASP67, TYR76, ALA73 and
ARG391 in AIA-II of sterol 14α-demethylase plays
important role in this receptor’s activity. Docking studies
performed by GLIDE has confirmed that above inhibitors
fit into the binding pocket of the DNA gyrase and sterol
14α-demethylase receptors was shown in the Figure 4 to
Figure 14. Finally we may observe that the successful
docking, intermolecular hydrogen bonding and lipophilic
interactions between the ligand and receptor. The key
cause for the increase in GLIDE score was due to the close
intra-ligand contacts.
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 RESEARCH ARTICLE

Table 1: The Docking Results of the Ligands against DNA Gyrase

S. No. Code Score Energy

1 AIA-2 -11.37 -74.08
2 DP-1 -8.53 -37.34
3 AIA-1 -8.94 -61.20
4 DP-3 -8.02 -47.97
5 DP-2 -6.05 -44.63
6 DP-4 -5.89 -57.23
7 Amikacin -13.88 -63.93
8 Ciprofloxacin -9.28 -30.59
9 Streptomycin -8.37 -33.86
0 Isoniazid -4.19 -22.47

Table 2: The Docking Results of the Ligands against Sterol 14α Demethylase

S. No. Code Score Energy

1 AIA-1 -11.13 -71.15
2 AIA-2 -10.07 -69.22
3 DP-2 -8.09 -40.79
4 HH-1 -7.49 -79.63
5 DP-4 -6.25 -47.90
6 DP-3 -6.28 -39.23
7 DP-1 -4.65 -28.09
8 Amikacin -9.87 -53.80
9 Ciprofloxacin -5.45 -28.53

CONCLUSION 7. Schnapp D, Reid C J, Harris A. Localization and expression of

The current study will be helpful for the progress of the
novel peptides against the bacteria’s and fungus. The
compounds AIA-II, DP-1 and AIA-I having tight binding and
more potent against the DNA Gyrase and the compounds
AIA-I, AIA-II, DP-2 and HH-1 having tight binding and more
potent against the sterol 14α-demethylase. These potential
drugs will be analyzed in wet lab based on the results
obtained by molecular docking.
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Cite this article as: Pandurangan Perumal, Vijay
Prakash Pandey. Docking Studies on Octa Peptides, Hexa
Peptides Related to Human Histatin and Apidaecin-IA
and Dipeptide against DNA Gyrase and Sterol 14α-
Demethylase. Inventi Impact: Molecular Modeling,
2014(4):173-178, 2014.

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