Solid State Technology

Volume: 63 Issue: 6
Publication Year: 2020

Effect of essential oil of Santalum album against

covid-19, lung cancer and streptococcal pneumonia:
an Insilco approach
G.N. Nirmala1, Akshata Sharma2, Dharani Dharan.K3, Venkatraghavan.R4
1,2,3
Department of Bioengineering, School of Engineering, Vels Institute of Science Technology and
Advance Studies (VISTAS), Pallavaram, Chennai-600117, Tamil Nadu, India
4
Department of Chemical Engineering, Alagappa College of Technology, Anna university, Chennai, Tamil
Nadu, India.
1
gnnirmala.se@velsuniv.ac.in

Abstract—The respiratory tract diseases are the leading cause of death worldwide. Considering the disease
related to the lower respiratory tract infections the mortality rate of lung cancer is 1.6 million every year
worldwide. The COVID-19 which is regarded as global pandemic has killed 1.34 million globally. Until
2017 about 2.56 million people had died due to bacterial pneumonia, therefore, targeting these diseases, the
present work aims to explore the potential of 35 bioactive compounds and essential oils from Santalum
album against the SARS CoV-2 spike protein (PDB Id: 7KJ3), asbestos carcinogenesis responsible human c-
Met Kinase (PDB Id: 2WD1), Streptococcus pneumoniae pneumolysin toxin (PDB Id: 5AOF) as drug
targets through in-silico molecular docking using AutoDock 4.2. Sixteen compounds were shortlisted for
molecular docking after screening through Lipinski’s rule of oral drug likeliness. The following compounds
α – Bergamotenol and cis - Lanceol showed the lowest binding energy of -8.170 and -8.164 kcals/mol out of
16 compounds tested against the SARS CoV-2 spike protein, Cis - Lanceol (-9.341 kcal/mol) and cis- α –
Santalol (-9.060 kcal/mol) were effective against the human c-Met Kinase, Cis- Lanceol (-7.362 Kcal/mol)
and dodecane (-7.186 kcal/mol) showed the highest potential against the S. pneumonia pneumolysin toxin.
The pharmacokinetic and toxicity properties of these compounds were predicted. Thus, these bioactive
compounds can further be investigated under in-vitro and in-vivo clinical trials to be used as potential drug
candidates
Keywords- Santalum album, AutoDock 4.2, SARS CoV-2, asbestos carcinogenesis, S. pneumoniae,
pneumolysin

I. INTRODUCTION
Respiratory diseases are one of the leading causes for deaths around the world, in which chronic
obstructive pulmonary disease is 3rd most common death cause in the world and another most common
respiratory disease is Asthma [1] included in the list is rare, yet lethal Asbestos carcinogenesis, enduring
Streptococcus pneumoniae and infamous COVID19. Asbestos carcinogenesis or also known as pleural
Mesothelioma is a rare form of cancer caused by long time Asbestos exposure of total of 45,221 malignant
mesothelioma deaths reported by CDC from 1999–2015 in the US [2]. Microscopic asbestos fibre is known
to cause inflammation and genetic change due to its inhalation, which affects c-Met Kinase [Hepatocyte
growth factor receptor], a protein found commonly in stem cells to form more cancerous cell and readily

20449
 Solid State Technology
Volume: 63 Issue: 6
Publication Year: 2020

promote metastasis mostly in pleura [lining of the lungs] of 70% to 75% cases [2][3][4]. c-Met Kinase
protein (PDB ID: 2WD1) is the first target protein for in-silico work.
Streptococcus pneumonia was responsible for 52% of total fatal pneumonia cases in children in 2016,
2018 study of Global Burden of Disease (GBD) [5][6], while approx. 2.56 million people causality was
reported in 2017 from pneumonia. Pneumolysin is a key virulent toxin produced by S. pneumonia which is
reported to induce lysis by pore formation on all cells containing cholesterol in its structure especially cell
membrane on reaching above 50 haemolytic units [7][8][9]. Apart from pore-inducing ability, pneumolysin
is reported to have a wide range of effects on host including immune cell inflammation, apoptosis of cells
with immense tissue damage throughout the body of the host [7]. Therefore, pneumolysin toxin (PDB ID:
5AOF) has been chosen as the second target protein. COVID 19 is wreaking havoc worldwide with more
than 60 million cases and the number of confirmed cases increasing day by day with the US leading by 13
million confirmed cases [10]. SARS-CoV-2 employs spike membrane glycoprotein which readily binds to
angiotensin-converting enzyme 2 (ACE2) protein in lung tissues causing virus-cell fusion which is
associated to the primary way of COVID19 infection [11]. Thus, spike protein (PDB ID: 7KJ3) consisting of
1234 AA is taken as the third target protein for in-silico work.
The Forest region between Karnataka and Tamil Nadu is endemic to Santalum album Linn or commonly
known as sandalwood covering 8300 square kilometres area [12]. S. album species are known for their fine
wood quality which is fragrant in nature, and thus was heavily exploited [13]. The fragrant wood is due to
the presence of oils reported mostly of sesquiterpenoids, monoterpenoids, phenolics, tannins, saponins, etc
[14][15]. Alcohols like cis α-santalol, β-santalol, epi-β-santalol, cis-lanceol, and trans-α-bergamotol are
reported to present while hydrocarbons such as α-Curcumene, α-Funebrene, α-santalene, β-santalene, β-
sesquiphellandrene, Bicyclogermacrene, Caryophyllene oxide, di-epi-α-cedrene, dodecene, epi-beta-
santalene and trans-α-bergamotene [14][15][16]. Santalum album extract is reported to have a decent 15 mm
zone of inhibition against Proteus Vulgaris [17] and also against many gram-positive including
streptococcus and Staphylococcus MRSA strain too [18]. S. album oil has been reported to show
antibacterial effect against Bacillus pumilis sp., Staphylococcus albus sp., Escherichia coli sp., Micrococcus
glutamicus sp., Salmonella paratyphi sp. [13]. S. album has been reported for anti-cancer activity due to the
chemo preventive effect of its oil in skin cancer, shown to arrest the cell cycle and induce apoptosis in J82
human bladder tumour cells, also against HL-60 human promyelocytic leukaemia tissues by inducing
cytotoxicity [19]. Sandalwood oil's ability to stop replication in Herpes Simplex Viruses-l and -2 was
reported [20]. β-santalol, a major constituent of S. album has shown anti-influenza A (H3N2) virus activity
at 86% efficacy with no cytotoxicity at 100 μg/mL concentration [21].
Other reported activity by application of S. album and its extract includes anti-inflammatory effect,
antifungal activity, antipyretic effect, etc [13]. With these as support, we attempt to perform molecular
docking of essential bioactive compounds from S. album against the binding site of the above-mentioned
target proteins and study their interactions and drug likeliness properties. This could be a road map for the
development of natural remedies from S. album and perform in-vitro studies in future.
II. MATERIALS AND METHOD

A. Determination of bioactive compounds of essential oil of Santalum album

The essential oil of Santalum album was subjected to phytochemical analysis which revealed the
presence of terpenoids that is, monoterpenoids and sesquiterpenoids, saponins, phenylpropanoid such as
phenolics, proanthocyanins, flavonoids, tannins, o-quinines and polyphenols [22]. Furthermore, the essential
20450
 Solid State Technology
Volume: 63 Issue: 6
Publication Year: 2020

oil was subjected to gas chromatography and Mass spectrometry analysis for the detection of bioactive
compounds which indicated the presence of 35 compounds. Several medicinal properties were reported on
the Sesquiterpenoids (α-Santalene and β-Santalene) and Santalol which shows inhibitory mechanism against
DNA polymerase, cancer cell (human colon carcinoma HCT116 growth inhibition, antiallergic and anti-
hexosaminidase activity. The epi-β-santalene was reported to be active against Salmonella typhimurium
[23].
B. Screening of protein and ligand library
The selection of bioactive compounds for molecular docking were based on the Lipinski rule of five
which involves five main parameters to be considered they are molecular weight
(<500), hydrogen bond donor (<5), hydrogen bond acceptor (<10), lipophilicity log P (<5) and molar
refractivity (40-130) and the compounds showing Ro5 violations were removed. Out of 35 bioactive
compounds 16 of them satisfied this Rule. Further, the structure of these compounds was retrieved from
PubChem server (https://pubchem.ncbi.nlm.nih.gov/) which is maintained by National Centre for
Biotechnology Information (NCBI). Additionally, the energy of each ligand was optimised to promote the
stability of the bioactive compound using Chimera software.
The proteins such as met kinase (2WD1), pneumolysin (5AOF) and SARS-COV-2 spike protein (7KJ3)
which are responsible for causing lung cancer, streptococcal pneumonia and corona virus disease
respectively was studied and retrieved from Protein Data Bank (PDB). A single chain was determined for
the docking analysis where the heteroatomic molecules, hydrophobic molecules were removed and the
further conformations was visualised using Pymol viewer. The protein binding site was predicted for each
protein by using Castp web server (http://sts.bioe.uic.edu/castp/index.html?3trg)[23][24].
C. Virtual ligand screening
The molecular docking was performed using Autodock 4.2 software. This software recognises the
binding efficiency of the ligand which is docked against the proteins that is, met kinase, pneumolysin and
spike protein. This software is made to understand the protein-protein interactions or protein ligand
interactions which is based on the Lamarckian genetic algorithm. The Autodock 4.2 is a two-step process
where the grid parameters are set by addition of hydrogen bonds and charges. The grid parameters were set
at dimensions (X:90Å Y:70Å Z:80Å) with grid points for the total map was 523341. The centre grid box
size was set with X axis: -1.750Å, Y axis: 1.444Å and Z-axis: -7.139 for met kinase protein (2DW1). For
pneumolysin (5AOF) the grid parameters were set at dimensions (X:56Å Y:62Å Z:60Å) with grid points for
the total map was 219051 and the centre grid box size was set with X axis: -5.611 Y axis: -13.333 and Z
axis: -21.917. For spike protein (7KJ3) the grid parameters were set at dimensions (X:60Å Y:66Å Z:63Å)
with grid points for the total map was 261568 and centre grid box was set with X axis: -19.417 Y axis:
30.194 and Z axis: -22.722. The default grid spacing was set same for all the proteins that is 0.375Å. The
interaction of the protein with their ligand forms the basis of the drug development process. The binding
energy is obtained for each ligand and the protein ligand complex was analysed using discovery studios
3.1[25],[26].
D. Discovery studios 3.1
The discovery studio 3.1 is a software which is used to visualise the 2D and 3D conformations of the
protein-ligand complex. This software helps to view the interactions such as Vander Waals interaction and
conventional hydrogen bonding. It also helps in visualising the surface images which shows the

20451
 Solid State Technology
Volume: 63 Issue: 6
Publication Year: 2020

conformation of structure-based ligand protein docking against the targeted proteins (met kinase,
pneumolysin and spike protein). Discovery studios 3.1 software is maintained by Dassault system [25],[27].
E. Prediction of pharmacokinetic properties and toxicity level of the drug
The pharmacokinetic properties like absorption, distribution, metabolism, excretion and toxicity level
were determined for the bioactive compounds of Santalum album essential oil which was reported by the
GC-MS analysis. These properties play a vital role to analyse the behaviour and characteristics of the drug
material such as water solubility, gastrointestinal absorption, the penetration level of drug molecule into the
blood brain barrier and central nervous system. The hepatotoxicity and skin permeability were also analysed
for both humans and rats. The ADMET properties were predicted using SwissADME webserver
(http://www.swissadme.ch/). This software works on the principle of vector-based algorithm which helps for
calculating the behaviour and characteristics of drug compounds [24],[27].
III. RESULTS AND DISCUSSION
The ligand binding site predicted using the Castp server is reported for all the three proteins. Prediction of
ligand-binding site using Castp revealed 31 amino acid residues of the protein human c-met kinase (PDB Id:
2WD1) that is TYR1159, MET1160, ALA1108 ,PRO1158, LEU1157, MET1211, VAL1092, TYR1230,
LEU1140, ARG1208, ALA1221, ALA1226, ASP1222, ILE1084, LEU1225, GLY1224, PHE1223,
ARG1203, HIS1202, VAL1201, PHE1200, GLU1127, PHE1124, GLN1123, GLU1120, ILE1115,
ARG1114, ASN1113, LEU1112, LYS1110, PHE1089, 18 residues of pneumolysin from Streptococcus
pneumoniae (PDB Id: 5AOF) which includes ASP41, GLU42, THR251, SER252, LYS253, SER254,
GLU275, GLN278, ILE279, ASN282, ALA355, ARG357, ASN358, LEU445,VAL446, ARG447, ASN468,
ALA470, and 23 residues of the newly released crystal structure of SARS-CoV-2 spike protein that is
VAL227, LEU226, ILE128, TRP104, VAL127, PHE192, SER205, GLU96, ASN121, VAL126, PHE194,
ARG102, ASN99, ILE119, VAL120, ARG190, ASN99, PHE92, ILE101, GLY103, GLU96, SER94,
ILE203.
The Lipinski satisfied 16 active essential compounds were docked against the 3 proteins (Table 2).
Molecular docking of essential compounds from Santalum album against the three proteins viz., 2WD1,
5AOF, and 7KJ3 were not previously reported.
A. Molecular docking of met kinase
Table 2 denotes the molecular docking of ligands from Santalum album against the human c-met kinase
protein revealed the top three compounds cis-lanceol with lowest binding energy of -9.341 kcal/mol and
inhibition constant Ki = 8.72 µM, followed by cis-α-santalol (-9.060 kcal/mol and Ki = 8.33 µM), α-
bergamotenol and (-8.923 kcal/mol and Ki = 10.35 µM). The binding energies of the rest of the compounds
were in the range of -8.892 to -6.409 kcal/mol respectively. This research work elucidates the binding and
chemistry of the top three lowest binding energy compounds docked with their respective targets. The lower
the binding energy, the higher is the affinity and stronger the interactions and inhibition. The docking of cis-
lanceol with human c-met kinase interacted with the following amino acids viz., PHE1089, LEU1112,
ASN1113, ARG1114, ILE1115, GLN1123, PHE1124, GLU1127, GLN1223, GLY1224, and ARG1227
during molecular docking. From these amino acids, PHE1124, ASN1113, and ARG1114 formed covalent
hydrogen bonds with the oxygen atoms of cis-lanceol within 3 Å (Fig 1). The oxygen atom in the carboxyl
terminal of PHE1124 was the hydrogen acceptor and the OH- on the tail end of the ligand was hydrogen
donor. The hydrogen bond is the strongest bond and play a vital role in supramolecular interactions, thus
more the number intermolecular hydrogen bonds, greater the inhibition efficiency. This is a strong bond
20452
 Solid State Technology
Volume: 63 Issue: 6
Publication Year: 2020

with an interatomic bond distance of 1.97 Å. The oxygen atom on the ligand was the acceptor and the -NH
on the residue ASN1113 was the electron donor with a bond distance of 2.8 Å. The -NH of ARG1114
residue donated its hydrogen to oxygen atom of cis-lanceol with a bond distance of 1.95 Å. The total
molecular solvent accessibility area was 3320.50 Ų. Moreover, other supramolecular interactions like alkyl,
π-alkyl, and Van Der Waals were also formed with LEU1112, ILE1115, PHE1124, and LEU1225.[28]. also
reported similar results pertaining to the present study where PHE1089 (3.4 Å) and ARG1114 (1.8 Å)
interacted in the ligand-binding site, however the binding energy was not reported [28]. Mady et al. studied
the inhibition and proliferation of human c-met kinase using meleagrin isolated from an endophytic fungus
Penicillium chrysogenum and reported the similar involvement of residues in the binding site similar to the
present work [29]. They also observed π-π stacks and hydrogen bond interactions took part in during the
docking. The compound cis-lanceol has reported to possess various properties like anti-inflammatory, anti-
oxidant, anti-cancer, anti-bacterial, and anti-fungal agents [30]. Cis-lanceol has inhibited the virulence of
various types of cancers and tumours under in-vitro conditions [19]. The compound cis-α-santalol when
docked against the human c-met kinase showed a binding energy -9.06 kcal/mol with an inhibition constant
value of 8.33 µM. Various amino acids namely, PHE1089, LYS1110, LEU1112, ASN1113, ARG1114,
ILE1115, PHE1124, GLY1224, LEU1225, LEU1225, and ARG1227 were found to interact with the ligand.
The total molecule solvent accessibility area for the docked complex was 3265.9 Ų. There were three
covalent hydrogen bond interactions formed with the carboxyl end of PHE1089 as the acceptor and a
hydrogen donor from of cis-α-santalol with a bond length of 1.94 Å. The other two hydrogen bonds were
formed with the residues ASN1113 and ARG1114 at a distance of 2.71 and 1.74 Å from the ligand
respectively. The -NH terminal of ASN1113 and ARG1114 actively participated as donor atoms and oxygen
atoms on the ligand as acceptors. Apart from the conventional hydrogen bonds, other weaker interactions
like alkyl and π-alkyl bonds were also formed during docking. All the supramolecular bonded and non-
bonded interactions between the amino acids in the binding site and ligand were formed within 2 Å bond
length, thus stronger the interactions. Molecular docking of bergamotenol against the human c-met kinase
showed a binding of -8.923 kcal/mol with a Ki value of 10.35 µM. The interactions were very similar to the
amino acids involved in the top two conformations. PHE1089, LEU1112, ASN1113, ARG1114, ILE1115,
PHE1124, GLY1224, LEU1225, and ARG1227 were found to interact with the ligand with molecule solvent
accessibility area of 3272 Ų. Once again, the same donor and acceptor atoms were involved in the
interactions forming hydrogen, alkyl, and π-alkyl bonds similar to cis-lanceol and cis-α-santalol with the c-
met kinase.
B. Molecular docking of Pneumolysin
Molecular docking of Streptococcal pneumolysin (PDB Id: 5AOF) revealed the following compounds
viz., cis-lanceol (-7.362 kcal/mol, Ki = 245.39 µM), dodecane (-7.186 kcal/mol, Ki = 970.93 µM), and epi-
beta-santalene (-6.914 kcal/mol, Ki = 86.30 µM) as the top compounds with good binding energies (Table
3). The compound cis-lanceol interacted with amino acids GLU42, THR251, SER252, LYS253, SER254,
ASP255, GLU275, GLN278, VAL353, THR354, ALA355, and ARG357 with 2825.84 Ų (Fig 2). There
were three hydrogen bonds formed between the protein and cis-lanceol within 3 Å viz., -NH terminal of
ALA355 interacted with oxygen acceptor of the ligand with a bond length of 2 Å. The second hydrogen
bond formed between the ligand and carboxyl terminal of LYS253 with a bond length of 2.58 Å. The third
bond was formed between the ligand and oxygen atom of carboxyl terminal of VAL353 with 2.03 Å bond
length. Other supramolecular interactions were alkyl bonds formed with LYS253 residue. Dodecane with a
binding energy of -7.186 kcal/mol ranked second against pneumolysin with the following with molecule
20453
 Solid State Technology
Volume: 63 Issue: 6
Publication Year: 2020

solvent accessibility area of 3075.57 Å interacting with TYR356, ARG357, GLY414, VAL416, ARG417,
LEU445, VAL446, ARG447, and ASN468 in the binding site. No conventional intermolecular hydrogen
bonds were observed during docking as there were no acceptor or donor atoms in the ligand. Van Der
Waals, alkyl, and π-alkyl interactions were formed TYR356, ARG357, LEU445, and ARG447 residues.
Epi-beta-santalene interacted with the following residues in the binding site of the protein viz., TYR356,
ARG357, ASN358, GLY414, VAL416, ARG417, LEU445, VAL446, ARG447, and ASN468 with a solvent
accessibility of 2819.67 Å. No conventional intermolecular hydrogen bonds were observed during docking
as there were no acceptor or donor atoms in the ligand. Van Der Waals, alkyl, and π-alkyl interactions were
formed TYR356, ARG357, LEU445, and ARG447 residues.
C. Molecular docking of SARS-CoV-2 spike protein
Targeting the SARS-CoV-2 spike glycoprotein (PDB Id: 7KJ3) using in-silico tools revealed the
following compounds with good binding energy, α-bergamotenol was the top ranked with -8.170 kcal/mol
and Ki = 36.21 µM, followed by beta-sesquiphellandrene with energy -7.850 kcal/mol and 35.24 µM, and
cis-lanceol with energy -8.164 kcal/mol and Ki = 48.27 µM. α-bergamotenol interacted with PHE92,
SER94, GLU96, ILE101, ARG102, GLY103, TRP104, ILE119, VAL120, ASN121, ARG190, and PHE192
amino acid residues with solvent accessibility area 3555.18 Ų (Fig 3) (Table 4). One conventional hydrogen
bond was formed between hydrogen donor of ligand and the acceptor oxygen atom in the carboxyl terminal
of the positive charged amino acid ARG102 at 2 Å. The other interactions were found to be Van Der Waals,
π-sigma, alkyl, and π-alkyl bonds. Cis-lanceol ranked the second interacting with SER94, GLU96, ILE101,
ARG102, GLY103, TRP104, ILE119, VAL120, ASN121, VAL126, PHE192, ILE203, SER205, LEU226,
and VAL227 with 3684.37 Å2. Three hydrogen were formed within 3 Å with GLU96 and ARG190 residues.
Other interactions were Van Der Waals, alkyl, and π-alkyl bonds. Beta-sesquiphellandrene interacted
PHE92, SER94, GLU96, ILE101, ARG102, GLY103, TRP104, ILE119, VAL120, ASN121, VAL126,
ILE128, PHE192, ILE203, and VAL227 residues. No intermolecular conventional hydrogen bonds were
observed. Supramolecular hydrophobic bonds like Van Der Waals, alkyl, and π-alkyl were only formed with
hydrophobic amino acids and aromatic or aliphatic group of the ligand. The molecular solvent accessibility
area for the interaction was 3750.13 Å2. The overall interactions were hydrogens, alkyl, and π-alkyl bonds
throughout all the proteins. Thus, these supramolecular interactions from S. album has shown good binding
energies and signs of inhibiting the virulence of the proteins human c-met kinase, Streptococcal
pneumolysin, and SARS-CoV-2 spike protein and this paves way to the experimental studies with the
compounds from Santalum album for in-vitro and in-vivo studies.
D. Screening of drug properties
The pharmacokinetic properties (Table 5 to 8) viz., absorption, distribution, metabolism, and excretion
properties of the top three compounds with the best binding energies against the three proteins were
reported. All the compounds showed very good gastrointestinal absorption properties above 90%. None of
the compounds were P-glycoprotein substrate and inhibitors. The compounds also showed satisfactory
blood-brain barrier and central nervous system permeability properties. The compounds were neither
CYP2D6 substrate nor CYP2C9, CYP2D6, and CYP3A4 inhibitors. Compounds α-Bergamotenol, β-
Santalol, Cis- α-Santalol, Epi-β-Santalene, and trans-β-begamotene were CYP3A4 substrates. The
compounds β-Santalol and cis- α-Santalol were CYP1A2 inhibitors and cis-lanceol was the inhibitor of
CYP2CI9. None of the compounds reported AMES mutagenic property and were not hERG I inhibitor. The

20454
 Solid State Technology
Volume: 63 Issue: 6
Publication Year: 2020

compounds were safe and were not hepatotoxic in nature. All compounds reported skin sensitisation
property.

IV. CONCLUSION
Thus, the essential oils from Santalum album were studied for their potentials against the three virulent
disease responsible proteins viz., human c-met kinase, Streptococcal pneumolysin, and SARS-CoV-2 spike
protein. The Insilico studies of essential oils from Santalum album was not done before against these
proteins. The compounds from S. album were shortlisted using Lipinski’s drug likeliness properties for oral
drug likeliness and a total of 16 compounds were selected for molecular docking using AutoDock 4.2.6. The
ligand preparation and energy minimization were performed using the UCSF Chimera 1.14 and saved. The
Castp server was used to predict the ligand-binding site of all the three proteins. Molecular docking was
performed and the results revealed the binding energies of bioactive compounds have shown potentials to
inhibit the proteins forming supramolecular bonded and non-bonded interactions. The amino acids and the
interactions formed were elucidated and studied. Majority of the compounds were not the inhibitors of
cytochrome enzymes expect few. The compounds were hepatotoxic at higher concentrations. No compounds
were genotoxic and are non-mutagenic in nature. The compounds were not inhibitors of hERG that is
responsible for cardiotoxic properties. The future studies will throw limelight on the experimental part that
is., in-vitro studies using the compounds that reported good binding energies.
CONFLICTS OF INTEREST
The conflicts of interest reported none.
ACKNOWLEDGEMENT
The authors sincerely thank Vels Institute of Science Technology and Advanced Studies for the successful
completion of the research work
REFERENCES
[1] https://www.who.int/gard/publications/The_Global_Impact_of_Respiratory_Disease.pdf
[2] https://www.cdc.gov/mmwr/volumes/66/wr/mm6608a3.html
[3] Brandi G, Tavolari S. Asbestos and intrahepatic cholangiocarcinoma. Cells. 2020 Feb;9(2):421.
[4] Toyokuni S. Mechanisms of asbestos-induced carcinogenesis. Nagoya J Med Sci. 2009 Feb 1;71(1-
2):1-0.
[5] Troeger C, Blacker B, Khalil IA, Rao PC, Cao J, Zimsen SR, Albertson SB, Deshpande A, Farag T,
Abebe Z, Adetifa IM. Estimates of the global, regional, and national morbidity, mortality, and
aetiologies of lower respiratory infections in 195 countries, 1990–2016: a systematic analysis for the
Global Burden of Disease Study 2016. The Lancet infectious diseases. 2018 Nov 1;18(11):1191-210.
[6] https://ourworldindata.org/pneumonia#citation
[7] Hirst RA, Kadioglu A, O'callaghan C, Andrew PW. The role of pneumolysin in pneumococcal
pneumonia and meningitis. Clinical & Experimental Immunology. 2004 Nov;138(2):195-201.
[8] Boulnois GJ, Paton JC, Mitchell TJ, Andrew PW. Structure and function of pneumolysin, the
multifunctional, thiol‐activated toxin of Streptococcus pneumoniae. Molecular microbiology. 1991
Nov;5(11):2611-6.
[9] ANDREW PW, MITCHELL TJ, Morgan PJ. Relationship of structure to function in pneumolysin.
Microbial Drug Resistance. 1997;3(1):11-7.

20455
 Solid State Technology
Volume: 63 Issue: 6
Publication Year: 2020

[10] https://www.who.int/emergencies/diseases/novel-coronavirus-2019
[11] Bosch BJ, Van der Zee R, De Haan CA, Rottier PJ. The coronavirus spike protein is a class I virus
fusion protein: structural and functional characterization of the fusion core complex. Journal of
virology. 2003 Aug 15;77(16):8801-11.
[12] http://www.frienvis.nic.in/WriteReadData/UserFiles/file/pdfs/Sandal.pdf
[13] Sindhu RK, Upma KA, Arora S. Santalum album linn: a review on morphology, phytochemistry and
pharmacological aspects. Intl J PharmTech Res. 2010 Jan;2(1):914-9.
[14] Burdock GA, Carabin IG. Safety assessment of sandalwood oil (Santalum album L.). Food and
Chemical Toxicology. 2008 Feb 1;46(2):421-32.
[15] Misra BB, Dey S. Comparative phytochemical analysis and antibacterial efficacy of in vitro and in
vivo extracts from E ast I ndian sandalwood tree (S antalum album L.). Letters in applied
microbiology. 2012 Dec;55(6):476-86.
[16] Jones CG, Plummer JA, Barbour EL. Non-destructive sampling of Indian sandalwood (Santalum
album L.) for oil content and composition. Journal of Essential Oil Research. 2007 Mar 1;19(2):157-
64.
[17] Khan UA, Rahman H, Niaz Z, Qasim M, Khan J, Tayyaba, Rehman B. Antibacterial activity of some
medicinal plants against selected human pathogenic bacteria. European Journal of Microbiology and
Immunology. 2013 Dec 1;3(4):272-4.
[18] Moy RL, Levenson C. Sandalwood album oil as a botanical therapeutic in dermatology. The Journal
of clinical and aesthetic dermatology. 2017 Oct;10(10):34.
[19] Santha S, Dwivedi C. Anticancer effects of sandalwood (Santalum album). Anticancer Research.
2015 Jun 1;35(6):3137-45.
[20] Benencia F, Courreges MC. Antiviral activity of sandalwood oil against herpes simplex viruses-1
and-2. Phytomedicine. 1999 May 1;6(2):119-23.
[21] Paulpandi M, Kannan S, Thangam R, Kaveri K, Gunasekaran P, Rejeeth C. In vitro anti-viral effect of
β-santalol against influenza viral replication. Phytomedicine. 2012 Feb 15;19(3-4):231-5.
[22] B.B. Misra1,2 and S. Dey. Comparative phytochemical analysis and antibacterial of in vitro and in
vivo extracts from East Indian sandalwood tree (Santalum album L.). Letters in Applied Microbiology
ISSN 0266-8254. doi:10.1111/lam.12005
[23] *Surendra Singh Bisht, Hemanthraj K.P.M. Gas Chromatography-Sass Spectrometry (GC-MS)
Profiling of Heartwood Oil Composition from 15 Years Old Sandalwood Trees. International Journal
of Pharmacognosy and Phytochemical Research 2014; 6(2); 387-392. ISSN: 0975-4873.
[24] Abhishek Biswal R, Vivek Pazhamalai*. A structure based molecular docking of Acacia catechu
against contractile protein Plasmodium falciparum – A Malarial Disease. Int. J. Pharm. Sci. Drug Res.
November-December, 2020, Vol 12, Issue 1.
[25] R. Abhishek Biswal, P. Jayashree, Kanna Mirunaalini, Vivek Pazhamalai*Molecular docking studies
of bioactive compounds from the leaves of Epiphyllum oxypetalum against Treponema pallidum,
Zika virus and liver cirrhosis
[26] R. Abhishek Biswal, Akshata Sharma, A. Aishwarya and Vivek Pazhamalai *MOLECULAR
DOCKING AND ADMET STUDIES OF BIOACTIVE COMPOUNDS OF RHIZOPORA

20456
 Solid State Technology
Volume: 63 Issue: 6
Publication Year: 2020

MUCORNATA AGAINST BACTERIAL ENZYME PROTEIN TYROSINE PHOSPHATASE.

IJPSR (2020), Volume 11, Issue 4
[27] Abhishek Biswal R, A. Aishwarya, Akshata Sharma, Vivek Pazhamalai*2D QSAR, Admet prediction
and multiple receptor molecular docking strategy in bioactive compounds of Gracilaria corticata
against Plasmodium falciparum (contractile Protein). Informatics in Medicine Unlocked 17 (2019)
100258.
[28] CJ S, MFB A. Vibrational, spectroscopic, chemical reactivity, molecular docking and in vitro
anticancer activity studies against A549 lung cancer cell lines of 5-Bromo-indole-3-carboxaldehyde.
Journal of molecular recognition: JMR. 2020 Oct 2; 1-20. http://doi.org/10.1002/jmr.2873.
[29] Mady MS, Mohyeldin MM, Ebrahim HY, Elsayed HE, Houssen WE, Haggag EG, Soliman RF, El
Sayed KA. The indole alkaloid meleagrin, from the olive tree endophytic fungus Penicillium
chrysogenum, as a novel lead for the control of c-Met-dependent breast cancer proliferation,
migration and invasion. Bioorganic & medicinal chemistry. 2016 Jan 15;24(2):113-22.
https://doi.org/10.1016/j.bmc.2015.11.038.
[30] Wintola OA, Afolayan AJ. Chemical constituents and biological activities of essential oils of Hydnora
africana thumb used to treat associated infections and diseases in south africa. Applied Sciences. 2017
May;7(5):443. https://doi.org/10.3390/app705044
Tables and figures

Table I: screening of bioactive compounds of santalum album oil using lipinski rule of five

Compound name Molecular Hydrogen Hydrogen Log p Molar

mass bond donor bond acceptor refractivity
(<10) (<5)
(<500) (<5) (40-130)

Dodecene 168 0 0 4.703 57.423

Dodecane 170 0 0 4.927 52.517

Tetradecane 198 0 0 5.707 66.751

Tetradecane 196 0 0 5.483 66.657

α-Santalene 204 0 0 4.414 64.582

Trans-α- 204 0 0 4.725 66.742

Bergamotene

β- 204 0 0 4.891 68.832

sesquiphellandrene

Epi-β-santalene 204 0 0 4.725 66.742

Cis-β-Farnesene 204 0 0 5.201 70.992

β-Santalene 204 0 0 4.725 66.742

Α-Funebrene 204 0 0 4.414 64.582

20457
 Solid State Technology
Volume: 63 Issue: 6
Publication Year: 2020

Α-Curcumene 202 0 0 4.844 68.258

Β-Farnesene 204 0 0 5.201 70.992

Pentadecane 212 0 0 6.097 71.368

Hexadecane 224 0 0 6.263 75.891

Hexadecane 226 0 0 6.487 75.985

Α-Santalol 220 1 1 3.387 65.994

Α-Bergamotenol 220 1 1 3.697 68.154

Β-Santalol 220 1 1 3.697 68.154

Di-epi-cedrene 204 0 0 4.414 64.582

Cis-Lanceol 220 1 1 4.007 70.314

Bicyclogermacren 204 0 0 4.725 66.742

e

Octadecene 252 0 0 7.043 85.125

Octadecane 254 0 0 7.267 85.499

Β-caryophyllene 220 0 1 3.936 66.263

oxide

Cycloeicosane 280 0 0 7.349 92.607

Eicosane 282 0 0 8.048 94.453

Vaccenic acid 282 1 2 6.108 87.087

Octadecanoic acid 284 1 2 6.332 87.181

Heneicosanol 312 1 1 7.410 100.482

Docosane 310 0 0 8.828 103.687

Docosene 308 0 0 8.604 103.593

Tetracosane 338 0 0 9.608 112.921

Table II: Docked Confirmations Of Bioactive Compounds Of Santalum Album Oil Against Lung Cancer
(Pdb Id: 2wd1)

Compound name Binding Vanderwaals No. of Hydrogen Inhibition Total number

Energy Interaction Hydrogen Interactions Concentration of residues
bonds (µM/mM)

α- Bergamotenol -8.923 ASN1113, 2 ARG1114, 10.35 µM ASN1113,

GLY1224 PHE1089 GLY1224,
ARG1114,
20458
 Solid State Technology
Volume: 63 Issue: 6
Publication Year: 2020

PHE1089
α- Curcumene -8.202 GLY1224 0 - 41.87 µM GLY1224
GLN1123 GLN1123
GLU1127 GLU1127
PHE1124 PHE1124
ARG1227 ARG1227
LYS1110 LYS1110
α- Funebrene -8.003 MET1116 0 - 57.59 µM MET1116,
PRO1158 PRO1158,
ASN1209 ASN1209,
ARG1208 ARG1208,
ASP1222 ASP1222
α-Santalene -7.660 GLN1123 0 - 22.80 µM GLN1123,
GLU1120 GLU1120,
ASN1113 ASN1113
β- Santalene -7.906 GLY1224 0 - 18.13 µM GLY1224,
ASN1113 ASN1113
β- Santalol -8.892 GLY1224 3 ARG1114 09.41 µM GLY1224,
GLY1090 PHE1089 GLY1090,
ASN1113 ARG1114,
PHE1089,
ASN1113
β- -8.277 GLU1120 0 - 26.17 µM GLU1120,
Sesquiphellandrene GLN1123 GLN1123
PHE1124 PHE1124,
GLY1224 GLY1224
ASN1113 ASN1113,
ARG1227 ARG1227
LYS1110 LYS1110
Bicyclogermacrene -7.043 ASN1113 0 - 06.88 µM ASN1113,
ARG1227 ARG1227
GLY1224 GLY1224,
LEU1225 LEU1225
PHE1124 PHE1124,
GLU1120 GLU1120
Caryophyllene -6.409 GLU1120 0 - 20.04 µM GLU1120,
oxide GLY1224 GLY1224
ARG1227 ARG1227,
PHE1089 PHE1089
Cis-α-Santalol -9.060 LYS1110 2 ARG1114 08.33 µM ARG1114,
GLY1224 PHE1089 PHE1089,
ILE1115 LYS1110,
ASN1113 GLY1224
ILE1115,
ASN1113
Cis- Lanceol -9.314 ASN1113 1 PHE1089 08.72 µM PHE1089,
ARG1114 ASN1113,
ARG1227 ARG1114,
GLY1224 ARG1227
GLU1127 GLY1224,
GLN1123 GLU1127
GLN1123
Di-epi-Cedrene -7.254 GLU1120 0 - 04.81 µM ASN1113,
GLN1123 ARG1114
GLU1127 ARG1227,
GLY1224 GLY1224
ARG1227 GLU1127,
LYS1110 GLN1123

20459
 Solid State Technology
Volume: 63 Issue: 6
Publication Year: 2020

Dodecane -7.545 GLU1120 0 - 01.03 mM GLU1120,

ARG1114 ARG1114
ASN1113 ASN1113,
LEU1225 LEU1225
ARG1227 ARG1227,
LYS1110 LYS1110
Dodecene -7.190 LYS1110 0 - 01.54 mM LYS1110,
ASN1113 ASN1113
PHE1124 PHE1124,
GLN1123 GLN1123
GLU1127 GLU1127,
GLY1224 GLY1224
Epi-β-Santalene -7.988 GLU1120 0 - 13.34 µM GLU1120,
GLN1123 GLN1123
ASN1113 ASN1113
Trans-α- -8.390 LYS1110 0 - 11.00 µM LYS1110,
Begamotene ASN1113 ASN1113
GLY1224 GLY1224
Table III: Docked Confirmation Of Bioactive Compound Of Santalum Album Oil Against Streptococcus
Pneumoniae (Pdb Id: 5aof)

Compound Bindin Vanderwa No. of Hydroge Inhibition Total no.

name g als Hydrog n concentrati of
energy Interactio en interacti on residues
ns bonds ons (µM/mM)
α- Bergamotenol -5.167 GLU256 3 ASP255 04.64 mM GLU256,
SER252 SER254 SER252
GLN278 GLU275 GLN278,
ASP255
SER254,
GLU275
α- Curcumene -4.447 VAL353 0 - 12.95 Mm VAL353,
ASP255 ASP255
ILE279 ILE279,
SER254 SER254
GLU42 GLU42,
SER252 SER252
ASN282 ASN282,
GLN 278 GLN 278
α- Funebrene -5.768 GLU275 0 - 933.69 µM GLU275,
SER254 SER254
SER252 SER252,
ASP255 ASP255
GLN278 GLN278
α- Santalene -5.527 GLU42 0 - 786.82 µM GLU42,
ASP255 ASP255
VAL353 VAL353,
THR354 THR354
SER254 SER254,
GLN278 GLN278
GLU275 GLU275,
SER252 SER252
β- Santalene -5.356 SER254 0 - 01.82 mM SER254,
SER252 SER252
GLU275 GLU275,
THR251 THR251
ASN282 ASN282,
GLN278 GLN278
20460
 Solid State Technology
Volume: 63 Issue: 6
Publication Year: 2020

GLU42 GLU42,
ARG357 ARG357
β- Santalol -5.839 GLU256 3 GLU275 01.14 mM GLU275,
SER252 SER254 SER254
GLU42 ASP255 ASP255,
GLU256
SER252,
GLU42
β- -6.559 GLU42 0 - 346.78 µM GLU42,
Sesquiphellandr ARG357 ARG357
ene THR251 THR251,
SER254 SER254
GLU275 GLU275,
GLN278 GLN278
SER252 SER252,
ASN282 ASN282
Bicyclogermacre -5.443 GLY414 0 - 78.00 µM GLY414,
ne VAL416 VAL416
ARG417 ARG417
Caryophyllene -5.820 VAL416 1 ARG357 54.22 µM VAL416,
oxide ARG417 ARG417
ALA355 ALA355,
ASN468 ASN468,
ARG357
Cis-α-Santalol -6.804 VAL416 1 ASN468 295.24 µM VAL416,
ARG417 ARG417
VAL446 VAL446,
ASN468
Cis-Lanceol -7.362 ASP255 2 VAL353 309.30 µM ASP255,
THR354 ALA355 THR354
SER252 SER252,
SER254 SER254
GLU42 GLU42,
THR251 THR251
ARG357 ARG357,
GLN278 GLN278
GLU275 GLU275,
VAL353
ALA355
Di-epi-Cedrene -5.646 GLU42 0 - 72.73 µM GLU42,
ASN282 ASN282
SER252 SER252,
GLN278 GLN278
SER254 SER254,
GLU275 GLU275
Dodecane -7.186 VAL416 0 - 970.93 µM VAL416,
ARG417 ARG417
GLY414 GLY414,
ASN468 ASN468
Dodecene -6.247 VAL446 0 - 08.86 mM VAL446,
ASN468 ASN468
GLY414 GLY414,
VAL416 VAL416
ARG417 ARG417
Epi- β- -6.914 ASN468 0 - 86.30 µM ASN468,
Santalene VAL446 VAL446
ASN358 ASN358,
GLY414 GLY414
VAL416 VAL416,
ARG417 ARG417
20461
 Solid State Technology
Volume: 63 Issue: 6
Publication Year: 2020

Trans-α- -6.620 ASN468 0 - 195.23 µM ASN468,

Begamotene VAL446 VAL446
ARG447 ARG447,
ASN358 ASN358
GLY414 GLY414,
VAL416 VAL416
ARG417 ARG417.
Table IV: Docked Confirmation Of Bioactive Compounds Of Santalum Album Oil Against Corona Virus-2
Spike Protein (Pdb Id: 7kj3)

Compound name Binding Vanderwaals No. of Hydrogen Inhibition Total no.

energy Interactions Hydrogen interactions concentration of
bonds (µM/mM) residues
α- Bergamotenol -8.170 SER94 1 ARG102 36.21 µM SER94,
GLU96 GLU96
ASN121 ASN121,
VAL120 VAL120
GLY103 GLY103,
ARG102
α- Curcumene -7.567 SER94 0 - 49.47 µM SER94,
GLU96 GLU96
GLY103 GLY103,
ARG190 ARG190,
ARG102 ARG102,
ASN121 ASN121
VAL120 VAL120
α- Funebrene -7.463 GLU96 0 - 66.26 µM GLU96,
SER94 SER94
ARG102 ARG102,
ASN121 ASN121
VAL120 VAL120
α- Santalene -7.345 SER94 0 - 44.45 µM SER94,
GLY96 GLY96
ARG102 ARG102,
GLY103 GLY103
ASN121 ASN121
β- Santalene -7.330 SER94 0 - 63.82 µM SER94,
GLY96 GLY96
ARG102 ARG102,
ASN121 ASN121
VAL120 VAL120
β- Santalol -5.141 GLU298 1 GLN314 04 mM GLU298,
ASN317 ASN317
THR315 THR315,
THR302 THR302
LYS304 LYS304,
GLN314
β- -7.850 SER94 0 - 35.24 µM SER94,
Sesquiphellandrene GLY96 GLY96
ARG102 ARG102,
GLY103 GLY103
VAL120 VAL120,
ASN121 ASN121

20462
 Solid State Technology
Volume: 63 Issue: 6
Publication Year: 2020

Bicyclogermacrene -6.234 SER94 0 - 26.95 µM SER94,

GLY96 GLY96
GLY103 GLY103,
ARG102 ARG102
ASN121 ASN121
Caryophyllene -6.241 SER94 0 - 26.62 µM SER94,
oxide GLY96 GLY96
ASN121 ASN121,
GLY103 GLY103
Cis-α-Santalol -7.587 GLY103 2 ASN121 92.34 µM GLY103,
ARG102 ASN121
ARG102
Cis-Lanceol -8.164 GLY103 1 GLU96 48.27 µM GLY103,
ARG102 ARG102
VAL120 VAL120,
ASN121 ASN121
SER205 SER205,
SER94 SER94
GLU96
Di-epi-Cedrene -6.218 ARG102 0 - 27.66 µM ARG102,
ASN121 ASN121
ASN99 ASN99,
GLU96 GLU96
SER94 SER94,
GLY103 GLY103
Dodecane -7.073 SER94 0 - 1.21 mM SER94,
GLY96 GLY96
ARG102 ARG102,
GLY103 GLY103
ARG190 ARG190,
PHE194 PHE194
Dodecene -6.875 PHE92 0 - 1.71 mM PHE92,
SER94 SER94
GLY96 GLY96,
ARG102 ARG102
GLY103 GLY103
Epi- β- Santalene -7.322 SER94 0 - 50.55 µM SER94,
GLY96 GLY96
ARG102 ARG102,
GLY103 GLY103
VAL120 VAL120,
ASN121 ASN121
Trans-α- -7.361 SER94 0 - 32.95 µM SER94,
Begamotene GLY96 GLY96
ARG102 ARG102,
GLY103 GLY103
ARG190 ARG190
Table V: Absorption Properties Of The Bioactive Compounds Of Santalum Album Oil

20463
 Solid State Technology
Volume: 63 Issue: 6
Publication Year: 2020

Compound name Water CaCo2 GI Skin P- P-

solubility permeability absorption permeability Glycoprotein Glycoprotein
(Log Log pabb in (%) (Log kp) substrate inhibitor
Mol/l) 10-6 cm/sec
α-Bergamotenol -4.469 1.484 94.986 -2.078 No No
β-Santalol -4.839 1.483 92.158 -1.962 No No
β- -6.055 1.408 94.668 -1.223 No No
Sesquiphellandrene
Cis- α-Santalol -4.396 1.448 92.422 -2.457 No No
Cis-Lanceol -4.411 1.508 93.99 -1.711 No No
Dodecane -6.673 -1.378 92.42 -1.329 No No
Epi-β-Santalene -6.47 1.394 93.401 -1.672 No No
Trans-β-Begamotene -5.968 1.395 96.229 -1.677 No No

Table VI: Distribution Properties Of The Bioactive Compounds Of Santalum Album Oil

Compound Name VDss Fraction BBB CNS

human (Log unbound permeability Permeability
L/Kg) (human) (Fu) (Log BB)
(Log PS)

α-Bergamotenol 0.663 0.217 0.72 -2.309

β-Santalol 0.472 0.186 0.697 -1.838

β-Sesquiphellandrene 0.633 0.236 0.787 -2.107

Cis- α-Santalol 0.648 0.202 0.76 -2.066

Cis-Lanceol 0.444 0.301 0.648 -2.451

Dodecane 0.528 0.197 0.863 -1.635

Epi-β-Santalene 0.666 0.118 0.838 -1.517

Trans-β-Begamotene 0.861 0.149 0.86 -1.988

Table VII: Metabolism Properties Of The Bioactive Compounds Of Santalum Album Oil

Compound Name CYP2D6 CYP3A4 CYP1A2 CYP2CI9 CYP2C9 CYP2D6 CYP3A4

Substrate Substrate Inhibitor Inhibitor Inhibitor Inhibitor Inhibitor

α-Bergamotenol No Yes No No No No No

β-Santalol No Yes Yes No No No No

20464
 Solid State Technology
Volume: 63 Issue: 6
Publication Year: 2020

β- No No No No No No No
Sesquiphellandrene
Cis- α-Santalol No Yes Yes No No No No

Cis-Lanceol No No No Yes No No No

Dodecane No No No No No No No

Epi-β-Santalene No Yes No No No No No

Trans-β- No Yes No No No No No
Begamotene

Table VIII: Excretion And Toxicity Level Of Bioactive Compounds Of Santalum Album Oil
Compound Name Renal AMES Max. hERG I Oral rat Oral rat Liver Skin
OCT2 Toxicity tolerated inhibitor (acute) (chronic) Toxicity sensitisation
dose

α-Bergamotenol 1.244 No 0.034 No 1.761 1.999 No Yes

β-Santalol 1.271 No -0.352 No 1.589 1.24 No Yes
β-Sesquiphellandrene 1.458 No 0.273 No 1.584 1.314 No Yes
Cis- α-Santalol 1.058 No -0.441 No 1.666 1.19 No Yes
Cis-Lanceol 1.528 No 0.467 No 1.687 1.179 No Yes
Dodecane 1.696 No 0.324 No 1.566 1.45 No Yes
Epi-β-Santalene 1.204 No -0.241 No 1.494 1.409 No Yes
Trans-β-Begamotene 1.176 No 0.084 No 1.68 1.367 No Yes

Fig 1: 3D (left) and 2D (right) interactions of cis-lanceol with human c-met kinase (PDB ID :2WD1)

20465
 Solid State Technology
Volume: 63 Issue: 6
Publication Year: 2020

Fig 2: 3D (left) and 2D (right) interactions of cis-lanceol with Streptococcal pneumolysin (PDB ID: 5AOF)

Fig 3: 3D (left) and 2D (right) interactions of α-bergamotenol with SARS-CoV-2 spike protein (PDB ID:
7KJ3

20466

View publication stats