IN SILICO MOLECULAR DOCKING OF VANILLIC ACID AGAINST APOPTOTIC
PROTEINS
Senthil. J, Janaki Devi. V1, Padma Priya. V1 Ashok. K* and Babu. M*,
*1Department of Microbiology and Biotechnology, Faculty of Arts and Science,
Bharath Institute of Higher Education and Research, Chennai, Tamil Nadu, India
ABSTRACT
The present molecular docking study can be useful for the design and development
of novel compound having better inhibitory activity against apoptotic proteins (Caspase-3
and Caspase-9). The docking scores were highest for Caspase-9 with 36.471 kcal/mol with
the stronger interaction followed by Caspase-3 (36.9 kcal/mol) and the LogP, lower
hydrogen bond counts, confirming the capability of the vanillic acid for binding at the
active site of the receptor. The results clearly show that the molecular docking mechanism
used to detect the novel anticancer inhibitor has been successfully obtained from a natural
polyphenolic compound.
Keywords: Vanillic acid, Discovery Studio, Caspase-3 and Caspase-9
INTRODUCTION
Vanillic acid (4-hydroxy-3-methoxybenzoic acid) (VA) is a polyphenolic
dihydroxybenzoic acid compound produced by secondary metabolism in plants and is widely
used in the food industry as a flavoring, food additive and preservative and in pharmaceutical
industries as analeptic drug (etamivan) (Fig. 1A and B). The pleasant vanilla scent is due to
the molecular structure corresponding to the oxidative form of vanillin aldehyde (vanilla).
VA can be found in many foods, including rice, wheat, mango, strawberries, sugar cane,
herbs and spices, beer, wine, tea and juices [1-30].
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Fig. 1: Vanillic acid A- 2D structure and B-3D structure
Taking together, these findings suggest that vanillic acid has beneficial properties
such as antimicrobial, hepatotoxicity, antioxidant, cardiovascular disease, hemorheological
effects, neuroprotective effects and antihypertensive [31-36]. The objective of the study is to
identify that apoptotic proteins fit to the domain and active sites, to assess the chemical and
physical properties of the protein, to analyze the potentiality of the therapeutic agents in
terms of their properties, to perform Docking of the proteins with a compound vanillin acid
and to evaluate the compound docking and active site binding.
MATERIALS AND METHODS
Preparation of protein structure
Apoptotic protein structures of Caspase-3 (Fig. 2 and 3) and Caspase-9 (Fig. 4 and 5)
were obtained from RCSB Protein Data Bank (http: //www. pdb. org). All water molecules
were removed and on the final stage hydrogen atoms were added to the target protein
molecule.
Caspase-3 (PDB ID 2DKO.A)
Gene: CASP3
Organism: Homo sapiens (Human)
BLAST sequence
>sp|P42574|10-28
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SKSIKNLEPKIIHGSESMD
FASTA sequence
>3KJF:B|PDBID|CHAIN|SEQUENCE
SGVDDDMACHKIPVDADFLYAYSTAPGYYSWRNSKDGSWFIQSLCAMLKQYADKL
EFMHILTRVNRKVATEFESFSFDAT
FHAKKQIPCIVSMLTKELYFYHHHHHHHH
Fig. 2: 3D structure of Caspase-3
Fig. 3: Caspase-3 protein sequence chain view
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Caspase-9 (PDB ID 2AR9)
Gene: CASP9
Organism: Homo sapiens (Human)
BLAST sequence
>sp|P55211|1-92
MDEADRRLLRRCRLRLVEELQVDQLWDALLSRELFRPHMIEDIQRAGSGSRRDQAR
QLII
DLETRGSQALPLFISCLEDTGQDMLASFLRTN
FASTA sequence
>2AR9:A|PDBID|CHAIN|SEQUENCE
MGALESLRGNADLAYILSMEPCGHCLIINNVNFCRESGLRTRTGSNIDCEKLRRRFSS
LHFMVEVKGDLTAKKMVLALLE
LARQDHGALDCCVVVILSHGCQASHLQFPGAVYGTDGCPVSVEKIVNIFNGTSCPSL
GGKPKLFFIQASGGEQKDHGFEV
ASTSPEDESPGSNPEPDATPFQEGLRTFDQLDAISSLPTPSDIFVSYSTFPGFVSWRDPK
SGSWYVETLDDIFEQWAHSE
DLQSLLLRVANAVSVKGIYKQMPCIVSMLRKKLFFKTS
Fig. 4: 3D structure of Caspase-9
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Fig. 5: Caspase-9 protein sequence chain view
Preparation of ligand structure
ChemSketch, chemically intelligent drawing interface freeware developed by
Advanced Chemistry Development, Inc., (http: //www. acdlabs. com).
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Physical and chemical properties of ligand were retrieved from
https://pubchem.ncbi.nlm.nih.gov/compound/8468.
The key results in a (Discovery Studio) docking log are the docked structures found at
the end of each run, the energies of these docked structures and their similarities to each
other.
RESULTS AND DISCUSSION
Fig. 6: Pharmacore model of vanillin acid against apoptotic proteins
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Fig. 7: Docked complex of vanillin against Caspase-3
Fig. 8: Docked complex of vanillin against Caspase-9
Table 1: Docking score of vanillin acid against apoptotic proteins
Name of the protein Ligand Lib docking score
KCal/mol
H-B
Caspase-3
Vanillin acid
36.9 4
Caspase-9 36.471 3
To study the binding mode of Vanillin acid interaction with apoptotic protein,
intermolecular flexible docking simulations were performed and. Energy values were
calculated from the docked conformations of the protein‐inhibitor complexes. Docking
studies yielded crucial information concerning the orientation of the inhibitors in the binding
pocket of the target protein. Several potential inhibitors have been identified through the
docking simulation. The binding affinity of the apoptotic proteins with the Vanillin acid was
measured by kcal/mol. The docking scores were highest for Caspase-9 with 36.471 kcal/mol
with the stronger interaction followed by Caspase-3 (36.9 kcal/mol.) as showed in the table 1
and Fig. 6, 7 and 8 Analysis of ligand binding interaction with the protein can be useful for
new preventive and therapeutic drug for cancer. The results obtained from this study would
be useful in both understanding the inhibitory mode as well as in rapidly and accurately
predicting the activities of new inhibitors on the basis of docking scores.
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Moreover, the apoptosis induced by the vanillin acid is mitochondrial mediated
pathway as shown in the figure 9.
Fig. 9: Apoptosis was mediated by mitochondrial pathway
For the first time, natural polyphenolic compound (Vanillin acid) is docked with
apoptotic proteins, which can bind to the active site of the protein and interfere with its
activity, thereby ensuring the anticancer activity of the vanillic acid. The docking study of the
results showed that the vanillin acid tested could be bound to the apoptotic proteins. The
results clearly show that the molecular docking mechanism used to detect the novel
anticancer inhibitor has been successfully obtained from a natural polyphenolic compound.
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CONCLUSSION
In this study, the molecular docking was applied to explore the binding mechanism
and to correlate its docking score with the activity of Vanillin acid. The results of our present
study can be useful for the design and development of novel compound having better
inhibitory activity against several type of cancer. These potential drug candidates can further
be validated in wet lab studies for its proper function.
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