1. TOP-LEAD IDENTIFICATION USING ENSEMBLE
BASED VIRTUAL SCREENING AND
PHARMACOPHORE DRUG DESIGN FOR
BREAST CANCER METASTATIC BETA ARRESTIN 2
Student: ÔNG ĐĂNG QUANG – BTBTIU10003
Supervisor: Dr. LÊ THỊ LÝ
International University
National University – HCMC
7. INTRODUCTION
β - ARRESTIN 2 INHIBITOR
ARRB2
progression of breast cancer
invasiveness
CXCR4-mediated chemotaxis
breast
cancer
metastasis,
migration.
extracellular-signal-
regulated kinase (ERK1/2)
Lysophosphatidic Acid (LPA)
protease-activated receptor-2
(PAR-2)
ARRB2 INHIBITOR
Li TT, et al. (2009), Michal AM, et al. (2011), Sun, Yue, et al.(2002), Ge, Lan, et al.(2004), Pampillo, et al.(2009), Alemayehu M, et al. (2013), Mills
GB, Moolenaar WH (2003).
11. RESULTS
β - ARRESTIN 2 SEQUENCE ANALYSIS
>95% identity
among 15
species.
Glaser, Fabian, et al. "ConSurf: identification of functional regions in proteins
by surface-mapping of phylogenetic information." Bioinformatics 19.1
(2003): 163-164.
12. RESULTS
3D STRUCTURE OF β – ARRESTIN 2
A B
blue is modeled structure
red is crystal structure of Bovin
Singh, Salam Pradeep, et al. "Prediction of the three-dimensional structure of serine/threonine protein kinase pto of Solanum lycopersicum by
homology modelling." Bioinformation 8.5 (2012): 212.
13. 3D STRUCTURE OF β – ARRESTIN 2
Z-SCORE
z-score value of the modeled structure is -7.17
Wiederstein M, Sippl MJ (2007) ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins.
Nucleic Acids Res 35: W407–410.
14. 3D STRUCTURE OF β – ARRESTIN 2
RAMACHARAN PLOT
- No. of residues in
favoured region: 333
(84.3%)
- No. of residues in
allowed region: 39
(9.9%)
- No. of residues in
outlier region: 23
(5.8%)
Wiederstein M, Sippl MJ (2007)
ProSA-web: interactive web service
for the recognition of errors in three-
dimensional structures of proteins.
Nucleic Acids Res 35: W407–410.
15. TOP 15 POTENTIAL DRUGS MOLECULES
RESULTS
Trott, O.; Olson, A.J., Autodock vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and
multithreading. J Comput Chem 2010, 31, 455-461.
16. TOP 15 POTENTIAL DRUGS MOLECULES
Wishart, David S., et al. "DrugBank: a comprehensive resource for in silico
drug discovery and exploration." Nucleic acids research 34.suppl 1 (2006):
D668-D672.
17. PHARMACOPHORE
GENERATION
Hydrogen Bond Donor
as green vectored spheres
Hydrogen Bond Acceptor
as red vectored spheres
Hydrophobic as yellow
spheres
β-Arrestin2 active site is
shown as green.
(for column 1 & 2)
(for column 3)
18. COMMON PHARMACOPHORE FEATURES
Hydrogen Bond Donor as green vectored spheres
Hydrogen Bond Acceptor as red vectored spheres
Wolber, Gerhard, and Thierry Langer. "LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening
filters." Journal of chemical information and modeling 45.1 (2005): 160-169.
19. RESULTS
MOLECULAR SIMULATION
Total energy profile of human β-Arrestin 2
Kresse, Georg, and Jürgen Hafner. "Ab initio molecular dynamics for liquid metals." Physical Review B 47.1 (1993): 558.
20. MOLECULAR SIMULATION
ROOT MEAN SQUARE DEVIATION & FLUCTUATION ANALYSIS
≈ 0.1 nm
or 1 Å
17000 (ps)
Brunger, Axel T., J. Kuriyan, and Martin Karplus. "Crystallographic R factor refinement by molecular dynamics." Science 235.4787 (1987): 458-460.
21. MOLECULAR SIMULATION
RADIUS OF GYRATION CALCULATION
≈ 0.05 nm
or 0.5 Å
Lindahl, Erik, Berk Hess, and David Van Der Spoel. "GROMACS 3.0: a package for molecular simulation and trajectory analysis." Molecular
modeling annual 7.8 (2001): 306-317.
22. RESULTS
TOP NOVAL DRUG CANDIDATES
AM: arithmetic means
HM: harmonic mean
Beigel, J. H.; Farrar, J.; Han, A. M.; Hayden, F. G.; Hyer, R.; de Jong, M. D.; Lochindarat, S.; Nguyen, T. K.; Nguyen, T. H.; Tran, T. H.; Nicoll, A.; Touch,
S.; Yuen, K. Y. Avian influenza A (H5N1) infection in humans. N. Engl. J. Med. 2005, 353 (13), 1374–1385.
23. THE BEST 2 DRUG CANDIDATES
Rank ID Min.
HM
(kcal/mol)
Predicted Ki
(µM)
AM
(kcal/mol)
SD
(kcal/mol)
1 26 -8.4 -7.682 2.669 -7.604 0.3
2 1 -8 -7.169 6.555 -7.071 0.33
Compound 26 Compound 01
25. - Examining 3D structure of human ARRB2 model.
- Screening Drugbank database entirely for ARRB2 potential inhibitors.
- Suggesting pharmacophore features for ARRB2 inhibitors.
- Suggesting 2 best potential drug molecules as ARRB2 inhibitors.
- Time
- Computational resources
- Practical results
- Running molecular simulation for ARRB2-inhibitor complex.
- Building more good drug molecules as ARRB2 inhibitors.
- Cooperate computational methods with practical results.
- Try different drug database such as NCI (National Cancer Institute).
ACHIEVEMENTS
LIMITATIONS
FUTURE PLANS
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32. The mean square fluctuation (MSF) is a measure of the deviation between the
position of particle i and some reference position.
where T is the time over which one wants to average, and is the reference
position of particle i. Typically this reference position will be the time-averaged
position of the same particle i, i.e.
Note that the difference between RMSD and RMSF is that with the latter the average is taken over time, giving a value for each particle i. With RMSD the average is
taken over the particles, giving time resolved values.
When a dynamical system fluctuates about some well-defined
average position, the RMSD from the average over time can be
referred to as the RMSF or root mean square fluctuation.
Hinweis der Redaktion
Range of free energy of binding:
-11.6 to -6.6 (kcal/mol)