Identification of potential breast cancer treatment drugs
Scott Lusher will provide background information for several of the steps.
Jan Klomp needs to define Spotfire file with
overexpressed fragments.
Spotfire must be installed @ CMBI - contact Bob
Herzberger.
Microarray
Normal vs Breast Cancer
Tissues
Students have to identify
overexpressed fragments
using Spotfire
Jan Klomp should send info on these 3 fragments
to Marc van Driel.
These should be defined so that Marc can
deselect 2 due to expression in e.g. brain using
GeneSeeker
Spotfire Results
3 fragments overexpressed
Students have to use a search tool
to identify which genes these 3
fragments correspond to.
Search Results
3 genes identified,
including ER
Using GeneSeeker, students have
to deselect 2 of the 3 fragments
due to expression in brain, e.g.
Teaching versions of SRS databases have to be
built (from now on called SRS_Teach modules) so
that e.g. the ER entry of SwissProt does not have
the link to the PDB, and that the PDB does not have
the Era structures. Gijst van Schaftenaar has to
define queries on different databases.
GeneSeeker Results
ER is identified
Using SRS_Teach, students have
to gather information on ER, from
basic information to structural
information (Pfam, HSSP, PDB).
ER should be indentified as NR
SRS Results
Knowledge of ER and NR
family
Retrieval and multiple sequence
alignment of PDB structures vs.
ERa sequence
Gert Vriend and Simon Folkerstma will implement
WhatTeach for Homology Modelling purposes
MSA Results
Structures of various NRs
Homology Modelling of ERa with
WhatTeach
Homology modelling
Results
ERa model
Identification of potential breast cancer treatment drugs
Gert Vriend will
implement a dedicated
WhatCheck module
ERa crystal structure is
given to students
Homology modelling Results
ERa model
Students have to
compare model to
crystal structure and
evaluate quality of both
using WhatCheck
Gijst van Schaftenaar has to build a ca 20 compound mol2
database with active and non active compounds, including
tamoxifen. Tamoxifen shoud be one of the best scoring
compounds in the next docking step
Basic understanding of
ERa crystal structure
FlexX docking of
compound library.
Comparison of docking
poses.
Students are provided
with in-house compound
library
Paul Verwer has to decide which MD simulation program to
use. MD shoud be run in advance and saved so that students
have the results immediately.
FlexX Results
Selection of 2 compounds,
including tamoxifen.
Preparation of MD
simulation runs for 2
selected compounds.
Run of Whatcheck on
optimised complexes
MD Simulation Results
Verification of improvement of
quality of complexes.
Identification of interacting
residues within complex
containing tamoxifen.
Comparison to Simon's
interacting residue
database
Interacting residues list
Verification of lack of OH-histidine
interaction in tamoxifen complex
Proposals for modification
of tamoxifen.
Optimisation results
Proposal of Dihydroxytamoxifen
Docking/MD of
dihydroxytamoxifen
Final docking results
Verification of improvement in interaction of
Dihydroxytamoxifen with ERa