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The Sigma-Aldrich screening
collection and fragment collection has been parsed into thiols. These have been further parsed
based on formal charge. Finally, the 3D structures have been created using
CORINA and have
been optimized with Gaussian (AM1),
and structures were docked into Estrogen Receptor Ligand Binding Domain in both forms, agonist (pdb code 1ERE)
and antagonist (pdb code 1ERR) using Autodock.
Binding score was recomputed using X-SCORE.
Molecular Weight and druglike scores were calculated with Pipeline PilotTM
(SciTegic, Inc.). Druglike score is based on a comparison to 5233 known drugs, using
a Bayesian statistics approach.
The Estrogen Receptor is a member of nuclear hormone receptor family.
The docking studies were done in the presence of Estradiol -natural ligand- in the binding site
and is a target of breast cancer drugs, as well as endocrine disruptor pollutants.
Structures of AM1 minimized compounds are visible from the website by clicking on the 2D image of the
molecule. The lowest energy (of 10) docked structures is also visible by
clicking on the Autodock energy values in both conformations (agonist and antagonist)and also all ten structures are visible by
clicking on the index number (last columns) in both agonist and antagonist forms. To simplify viewing, for Autodock energies,
only docked ligand, helixes 11 and 12, and Estradiol are sown. The entire Estrogen Receptor Ligand Binding Domain, Estradiol and the 10 conformations
can be seen by clicking the Indexes.
Also 99 representatives thiols are available and will be subjected to experimental validation
for ER binding using STD NMR-based assays (comming soon).
Warning:
to see 3D structures, you need the Chime plugin from MDL
!!
Note: Autodock values for docked energy are in KCal/mol units. X-Score values are in pKd units.
For X-Score you have to multiply that value with -2.303RT (or -1.364) to get the values in KCal/mol units.
Thiols from Sigma Aldrich Screening Collection
FC = -2 Formal charge -2.
FC = -1 Formal charge -1.
FC = 0 - Part 1 Formal charge 0 - Part 1.
FC = 0 - Part2 Formal charge 0 - Part 2.
FC = 0 - Part 3 Formal charge 0 - Part 3.
FC = 1 Formal charge 1.
FC = 2 Formal charge 2.
Thiols from Sigma Aldrich Fragments Collection
FC = -2 Formal charge -2.
FC = -1 Formal charge -1.
FC = 0 Formal charge 0.
FC = +1 Formal charge +1.
FC = +2 Formal charge +2.
Estrogen Receptor LBD agonist (pdb code 1ERE) vs antagonist (pdb code 1ERR).
Close view and full LBD.
The CPFM has as part
of its mission, the goal of providing tools to help Medicinal Chemists
design protein inhibitors more effectively, either as drug leads or as
tools for studying protein function. To learn more about the CPFM, visit
our website at CPFM.
This work was sponsored by grant from the Department of Defence-Breast Cancer Research Program
(Grant # W81XWH-05-1-0476).
Prepared by Aurora D. COSTACHE in the SEM lab. (9/2006)
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