Combination of Fast Docking and Molecular Dynamics to Hit New Leads' Application to a Search of Fact - PowerPoint PPT Presentation

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Combination of Fast Docking and Molecular Dynamics to Hit New Leads' Application to a Search of Fact

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X-ray structure of a target enzyme is the first step on the way of the ... Galina Dubinina, Maxim Platonov, Dmytro Kovalskyy, Petro Borisko, Andriy Tolmachov ... – PowerPoint PPT presentation

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Title: Combination of Fast Docking and Molecular Dynamics to Hit New Leads' Application to a Search of Fact


1
Combination of Fast Docking and Molecular
Dynamics to Hit New Leads. Application to a
Search of Factor Xa Inhibitors
Galina Dubinina, Maxim Platonov, Dmytro
Kovalskyy, Petro Borisko, Andriy Tolmachov
Conformational flexibility of a target enzyme
may play a crucial role in determination of the
binding modes during virtual docking. We have
evaluated flexibility of the apo form of Factor
Xa during 5 ns-long molecular dynamics
simulation.
X-ray structure of a target enzyme is the first
step on the way of the development of specific
and potent inhibitors. We used crystal structure
of Factor Xa in complex with RPR128515 for the
docking study.
Enamine DataBase 290 000 compounds
Drug like and Pharmacophore Model
Filter SchrödingerTM
Schematic representation of the FXa/RPR12815
complex (PDB entry 1eqz)
A formation of the new binding pocket (green
initial conformation)
S1
S1
High-Throughput Docking Scoring Function
Filter Visual Inspection
S4
new pocket
Example of the compound that binds to the new
pocket
Example of the compound that binds to the S1 and
S4 pockets
In vitro assay FXa Targeted Library
  • Overview
  • 290000 compounds processed
  • Over 115000 virtually screened
  • 1400 passed in vitro tests (FXa)
  • 44 hit rate
  • 3 new scaffolds found
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