In sillico 2 send
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In Silico study of methyltransferase inhibitor’s effects on dengue virus
Gustavo A MartinezJuan E MaldonadoStudent Mentor: Dr. Hector Maldonado
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Prologue: Dengue Fever• Life threatening disease caused by Dengue Virus
– Dengue Fever– Dengue hemorrhagic fever– Dengue Shock Syndrome
• Many People are affected:– 2.5 billion are at risk – Locally, 12,580 cases reported (CDC 2010)
• Transmitted by the bite of an Aedes mosquito infected with any one of the four dengue viruses
• No approved treatment or prevention
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Prologue: Dengue virus• The dengue viruses are single-stranded RNA viruses• Four serotypes:
– DENV-1– DENV-2– DENV-3– DENV-4
• They belong to the family Flaviviridae and the genus Flavivirus– Other members of the family include:
• West Nile virus• Yellow Fever virus• Japanese Encephalitis virus• St. Louis Encephalitis virus
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Prologue: Methyltransferase• A family of enzymes that catalyze the transfer of
a methyl group from a donator to an acceptor• These methyl groups are important for
controlling genes in different types of cells• This methyl group is usually obtained from SAM
(S-Adenosyl methionine)• The energy necessary for these processes comes
from GTP
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Introduction• What would happen if GTP does not reach the
methyltransfarase?– The protein will not have any source of energy to
complete the transfers.– If there are no more transfers of methyl groups, then
the DNA will not be properly sequenced.
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Hypothesis
“Utilizing a high affinity compound to block the GTP from reacting, In Sillico research will reveal
how to disable the methyltransfare’s capabilities, ceasing viral production.”
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Hypothesis (2)
Through In Sillico study, the GTP can be inhibited by a higher affinity compound, resulting in the
cease of production of the Dengue virus
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Methodology Software Used:• PyMOL Molecular Graphics System v1.3 http://www.pymol.org• AutoDock (protein-protein docking software) http://autodock.scripps.edu/• Auto Dock Tools: Graphical Interfase for AutoDock
http://mgltools.scripps.edu/downloads• LigandScout: Advanced Pharmacophore Modeling and Screening of Drug
Databases. http://www.inteligand.com/ligandscout/
Databases Used:• National Center for Biotechnology Information (NCBI), Basic Local Alignment
Search Tool (BLAST) http://www.ncbi.nlm.nih.gov/blast/Blast.cgi• Research Collaboratory for Structural Bioinformatics (RCSB) www.pdb.org• ZINC: A free database for virtual screening: http://zinc.docking.org/
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DENV2: 2P1D Protein - Clean
Protein clean
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GIF Protein with colors
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GTP
SAH
GTP
RNAbinding site
SAH
F25
D146
K61
K180
E216
2P1D.pdb DENV2 Methyltransferase
Three Benzenes were determined to be in the hotspots
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Ben 230
Ben 01
Ben 267
01
230 267
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Rank Compound Affinity1 DENV-M2_1 -10.42 DENV-M2_2 -10.33 DENV-M2_3 -10.24 DENV-M2_4 -10.25 DENV-M2_5 -10.26 DENV-M2_6 -10.27 DENV-M2_7 -10.18 DENV-M2_8 -10.19 DENV-M2_9 -10.1
10 DENV-M2_10 -1011 DENV-M2_11 -1012 DENV-M2_12 -1013 DENV-M2_13 -1014 DENV-M2_14 -1015 DENV-M2_15 -1016 DENV-M2_16 -9.917 DENV-M2_17 -9.918 DENV-M2_18 -9.919 DENV-M2_19 -9.920 DENV-M2_20 -9.921 DENV-M2_21 -9.922 DENV-M2_22 -9.923 DENV-M2_23 -9.924 DENV-M2_24 -9.825 DENV-M2_25 -9.8
-10.4 1-10.3 1-10.2 4-10.1 3
-10 6-9.9 8-9.8 20-9.7 29-9.6 41-9.5 49
162
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Results
• For the three benzene rings, many compounds were found that could fit in the pocket.
• The top three with the most affinity were chosen:– ZINC00946278– ZINC04112974– ZINC04994141
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DENV-M2_1 DENV-M2_2 DENV-M2_310.05
10.1
10.15
10.2
10.25
10.3
10.35
10.4
Binding Energy
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GTP
SAH
GTP
RNAbinding site
SAH
F25
D146
K61
K180
E216
2P1D.pdb DENV2 Methyltransferase
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Conclusion
• Of the compounds with the most affinity, DENV-M2_1 was chosen because of its affinity of -10.4
• This compound showed to occupy the best within the methyltransferase.
• Also, this compound was the one that positioned itself within the protein in a manner similar to the benzene circles.
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Acknowledgements