this is for holding javascript data
David Koes added ER_a_p_ER_a__.tex
over 8 years ago
Commit id: d33d26cf23c95fd49afaef94fc0a8318c1975102
deletions | additions
diff --git a/ER_a_p_ER_a__.tex b/ER_a_p_ER_a__.tex
new file mode 100644
index 0000000..e2d2aea
--- /dev/null
+++ b/ER_a_p_ER_a__.tex
...
ER-a-p
ER-a with its best approach and SMARTS expression did not perform significantly better than random performance for the FOMS or VAMS method (cite table). Although FOMS was significantly better performing than VAMS, it still did not perform well enough for ER-a agonists to be considered an effective screening method.
Similar to ER-a, the interaction with Glu353 and Arg394 is vital for agonism of ER-a (cite crystal ER-a). There is also an indication that the stereochemistry is an important consideration for ER-a agonism when trying to avoid steric clash with W383, L536, and L539. The study reporting the crystal structure of the ER-a agonist cites, “…dihydrobenzoxathiin SERAMs [are] highly dependent on size and location of side chain substituents” (cite part 9). For this reason, it makes sense that our SMARTS expressions and fragment pre-alignments did not perform significantly better than random chance (cite table).
Docking of 1XP9 and its active set from MUV was performed using smina, and the two main interactions observed were with Glu353 and Arg394 concurrently (visual inspection). This indicates that both residues are important interactions for an ER-a agonist. In addition, there were 5 pockets available for filling. Three of these pockets were occupied by almost every conformer of the active compounds, with one of the main pockets being covered by fragment pre-alignment. The variation in which pockets needed to be filled indicates that there are a plethora of hydrophobic interactions that need to occur for ER-a agonism. This could explain the poor performance of both methods since it only pre-aligned to one of the many pockets.
For ER-a agonists, more specific SMARTS expressions had better performance for FOMS and VAMS (cite table). The best performing SMARTS expression covered the interaction with Glu353 and Arg394. This is what most likely gave it the best performance since interaction with these two residues are vital for ER-a agonism. (explanation for VAMS performance)
