Professional Documents
Culture Documents
Anti Cancer Activity Prediction of Secondary Metabolites From Marine Sponge Discodermia Calyx: An in Silico Approach
Anti Cancer Activity Prediction of Secondary Metabolites From Marine Sponge Discodermia Calyx: An in Silico Approach
A molecular docking analysis was carried out followed by Molecular Dynamics (MD) simulation studies on the
secondary metabolites from a marine sponge Discodermia calyx in order to identify their bioactive targets acting towards
cancer. Over expression of Epidermal Growth Factor Receptor (EGFR) results in triple negative breast cancer. Hence, a
docking investigation was carried out in order to predict the anticancer properties of secondary metabolites from a marine
sponge D. calyx targeting the EGFR. The compounds were further subjected to MD simulation analysis. Docking analysis
reveals that the compounds debromohamacanthin B, tetrahydrofurospongin and deoxytopsentin showed good interaction
with the EGFR receptor forming hydrogen bonds with the tyrosine and arginine residue preventing the binding of EGF to
the EGFR receptor by inhibiting dimerization with a score of 130.13, 139.369 and 114.416 respectively.
[Keywords: Discodermia calyx, EGFR, MD simulations, Docking, Triple negative breast cancer]
In the 2:2 EGF: EGFR complex, each EGF molecule is was then subjected to a 5 picoseconds (ps) heating
bound to only one of the two EGFR molecules, two 1:1 step from 0 to 300 K, a 150 ps equilibration step at
EGF: EGFR complexes are dimerized12. 300 K, and finally 150 ps of full MD production at
18 secondary metabolites (Table 1) reported 300 K with NPT ensemble. All simulation steps were
to be isolated from the sponge D. calyx was run with a time step of 1 fs. Full MD trajectory was
collected after literature survey2,13. The structure of considered for analysis. Interaction energy of
the 18 metabolites was drawn in ACD Chemsketch14 inhibitors with each individual residue in the binding
and was saved in .mol format in order to use as input site was estimated on the Simulation package.
for ligand set for docking studies.
Results and Discussions
Docking analysis was done using Accelrys
The protein structure was downloaded from PDB
Discovery Studio and the results in terms of hydrogen
and was docked with the prepared ligand set of
bonding and the scoring functions were noted. In
18 secondary metabolites from D. calyx. Of the
order to investigate further details of the interactions
18 compounds docked with the EGFR receptor there
between the protein and the ligand MD simulation
were 3 compounds namely Debromohamacanthin B,
was performed using the Simulation package in
tetrahydrofurospongin and deoxytopsentin showed
Discovery Studio 2.115 (Accelrys Inc., CA) with
interaction by binding at the EGF binding site
CHARMm force field. Briefly, the complex was
residues with a dock score of 130.13, 139.369 and
solvated in a water spherical boundary with harmonic
114.416 thereby preventing the binding of EGF to the
restraint using an inhibitor as a centre of mass and
EGFR receptor by inhibiting dimerization (Figs 2-4).
subsequently energy-minimized by the steepest
descent and conjugate gradient methods until the
system reached 0.001 kcal/mol convergence. System
Fig. 2Interaction of EGFR with Debromohamacanthin B with a Fig. 4Interaction of EGFR with deoxytopsentin with a docking
docking score of 130.13 forming a total of five H bonds score of 114.416 forming a total of four H bonds
RAJ & INBAKANDAN: ANTI CANCER ACTIVITY PREDICTION OF SECONDARY METABOLITES 655
Table 1List of the metabolites from D. calyx under study (Courtesy: Dr. Jee H. Jung)
S no. Name of the metabolite Structure
1 Ent-kurospongin
2 Tetradehydrofurospongin-1
3 Deoxytopsentin
4 Isobromodeoxytopsentin
5 Bromodeoxytopsentin
6 cis-3,4-Dihydrohamacanthin B
7 Hamacanthin B
8 6-Debromohamacanthin B
contd
656 INDIAN J. MAR. SCI., VOL. 42, NO. 5, SEPTEMBER 2013
Table 1List of the metabolites from D. calyx under study (Courtesy: Dr. Jee H. Jung) contd
S no. Name of the metabolite Structure
9 HamacanthinA
10 6-DebromohamacanthinA
11 Icadamide C
12 Icadamide A
13 Theopedrin K
14 Theopedrin L
15 Mycalamides A
16 Mycalamides B
contd
RAJ & INBAKANDAN: ANTI CANCER ACTIVITY PREDICTION OF SECONDARY METABOLITES 657
Table 1List of the metabolites from D. calyx under study (Courtesy: Dr. Jee H. Jung) contd
S no. Name of the metabolite Structure
17 Icadamide S
18 Icadamide A
3 Wakimoto T, Matsunaga S, Takai A, Fusetani N, Insight into 10 Franklin M C, Carey K D, Vajdos F F, Leahy D J,
Binding of Calyculin A to Protein Phosphatase 1, Chem Biol deVos A M, Sliwkowski M X, Insights into ErbB signaling
9 (2002) 309-319. from the structure of the ErbB2-pertuzumab complex,
4 Smith III B A, Beauchamp J T, LaMarche J M, Cancer Cell, 5(4) (2004) 317-28.
Kaufman D M, Qiu Y, Arimoto H, Jones R D, Kaoru 11 Bernstein F C, Koetzle T F, Williams G J, Meyer Jr. E E,
Kobayashi, Evolution of a Gram-Scale Synthesis of Brice M D, Rodgers J R, Kennard O, Shimanouchi T,
(+)-Discodermolide, J Am Chem Soc, 36 (2000) 8654-8664. Tasumi M, The Protein Data Bank: A Computer-based
5 Chen G, Luo X, Zhu W, Luo C, Liu H, Puah C M, Chen K, Archival File For Macromolecular Structures, J of Mol Biol,
Jiang H, Elucidating inhibitory models of the inhibitors of 112 (1977) 535.
epidermal growth factor receptor by docking and 3D-QSAR, 12 Ogiso H, Ishitani R, Nureki O, Fukai S, Yamanaka M,
Bioorg Med Chem, 12(9) (2004) 2409-17. Kim J H, Saito K, Inoue M, Shirouzu M, Yokoyama S,
6 Cavasotto C N, Ortiz M A, Abagyan R A, Piedrafita F J, In Crystal structure of the complex of human epidermal
silico identification of novel EGFR inhibitors with growth factor and receptor extracellular domains, Cell
antiproliferative activity against cancer cells, Bioorg Med (Cambridge,Mass.), 110(6) (2002) 775-787.
Chem Lett, 16(7) (2006) 1969-74.
13 Shinde P B, Mansoor T A, Luo X, Hong J, Lee C O,
7 Cho H S, Mason K, Ramyar K X, Stanley A M, Gabelli S B,
Jung J H, Cytotoxic Polyketides from the Marine Sponge
Denney D W, Leahy D J, Structure of the extracellular region Discodermia calyx, Bull Korean Chem Soc, 28(6) (2007)
of HER-2 alone and in complex with the Herceptin Fab, 990-994.
Nature, 421 (2003) 756-760.
8 Lee K, Kim J, Jeong K W, Lee K W, Lee Y, Song J Y, Kim M 14 ACD/ChemSketch Freeware, version 10.00, Advanced
S, Lee G S, Kim Y, Structure-based virtual screening of Src Chemistry Development, Inc., Toronto, ON, Canada,
kinase inhibitors, Bioorg Med Chem, (2009) vol. 17(8) 3152-61. www.acdlabs.com, 2012.
9 Mitsudomi T, Yatabe Y, Epidermal growth factor receptor in 15 Accelrys Software Inc., Discovery Studio Modeling
relation to tumor development: EGFR gene and cancer, Environment, Release 3.1, San Diego: Accelrys Software
FEBS J, 277(2) (2010) 301-8. Inc., 2011.