Secondary Target Identification for Neuraminidase Inhibitor Drugs

1
Secondary Target Identification for Neuraminidase
Inhibitor Drugs

• Michael Wang
• PRIME
• July 18, 2008
• Computer Network Information Center
• Beijing, China

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Project Goals

• Strategy for secondary target identification
• SMAP (SOIPPA Algorithm) Target the druggable
  human proteome with known structural homologues
• TarFisDock
• Program simulates binding of drugs to database
  proteins
• Proteins are ranked based on best energetic
  interactions
• Disadvantage does not take into account protein
  flexibility
• To take advantage of Autodock4s flexible
  receptor feature to support receptor flexibility.
  To refine the target selection criteria by
  ensuring the proper parameterization of the
  druggable proteome.  Additionally, I will use
  known NA inhibitors and all known neuraminidases
  from different species, especially humans, with
  crystal structures as my initial test set.
• Selectivity of known Neuraminidase Inhibitors
  against viral subtypes
• Make comparative studies of the NA inhibitors
  against other potentially pandemic subtypes, such
  as N2, N7
• Classify the previously identified top 27 hits in
  terms of their specificity for group-1, group-2
  enzymes, and in particular the N2 and N7 enzymes
• Use Autodock4 to establish the parameters for
  optimal binding conditions through redocking of
  ligands from known crystal structures, using
  conditions previously characterized for N1 as a
  starting point.
• Neuraminidase virtual screening hits and
  Polymorphism
• Study the effects of polymorphism in
  neuraminidase and examine the interaction of
  oseltamivir with the R41Q mutant, situated near
  the active site of sialic acid, by using Autodock
  and Modeler
• Confirm validity using Procheck, WHATIF, and
  SCWRL to examine the selectivity for different
  neuraminidases inhibitors with this particular
  phenotype

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Progress

• Obtained a list of druggable human proteins from
  Jacob Durrant
• Got SMAP to run successfully after editing
  scripts and revising commands
• Finished setting up SMAP environment by changing
  parameters in .sh shell script
• Edited parameters in pdbdefault.properties and
  smap.properties
• Recompiled qhull source code and placed it in the
  qhull linux directory within the SMAP
  distribution
• Installed and configured JDK 1.6 on the server
• Completed setup for MySQL database in order to
  match known ligand-binding sites
• Contacted Dr. Lei Xie regarding running larger
  datasets for SMAP
• Emailed developers of Autodock regarding program
  compatibility with different operating systems

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Work to be done

• Figure out how to run SMAP by setting the query
  output with the druggable human proteome instead
  of with a single query chain
• Analyze and understand the resulting output
  values for SMAP results
• Create an Excel Spreadsheet for a data
  compilation of structural alignment between
  ligand-binding sites, Z-scores, Raw-scores,
  Tanimoto Coefficients and RMSD values
• Successfully load Autodock Tools on my OS in
  preparation for evaluating optimal binding
  conditions of neuraminidase inhibitor drugs and
  neuraminidases
• Generate mol2 file for oseltamivir and other
  inhibitor drugs in preparation for reverse
  docking analysis through TarFisDock web service.

5
Summer Palace ???
6
Lao She Tea House ????
7
Beijing Zoo ?????
Badminton ???