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David Koes added ER_a_ER_a_with__.tex
over 8 years ago
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ER-a
ER-a with its best approach and SMARTS expression performed significantly better than random performance for FOMS (cite stat table). For the VAMS method, the best approach and SMARTS expression for ER-a was not significantly better than random performance (cite stat table). This indicates that for ER-a, FOMS was a better performing screening method.
The most important interaction for an ER-a inhibitor is the 3-hydroxy interaction with Glu 353 and stacking effect of the phenyl group with Phe 404 (cite crystal, ER-a). Although these interactions were covered by our SMARTS expression and fragment pre-alignment, another important interaction occurring between a 17-hydroxy group and His 524 was not covered by either our SMARTS selection or fragment pre-alignment (cite crystal ER-a). Higher selectivity can also come from the addition of a group that performs hydrogen bonding with Leu 384. Because only two of the important interactions that ER-a inhibitors need to perform are covered by the SMARTS and pre-alignment, it makes sense that FOMS did not perform better than random chance (refer to Table I will make).
When docking with smina was performed on 2IOG and its set of active compounds from MUV, the two main interactions observed were with Glu353 and Arg394 by one hydrogen-bond donor/acceptor (visual inspection). This indicates that both residues are important to interact with for an ER-a inhibitor. Our fragment selection and pre-alignment covered this interaction. There were also interactions with Asp351 observed on the distal side with a hydrogen-bond donor, sometimes concurrent with the previous interactions. This indicates that this interaction is also key for the binding mode of ER-a inhibitors, and was not covered by our fragment pre-alignment. There were also 5 pockets that could potentially be filled. Our pre-alignment only covered the most occupied pocket among all active conformers docked.
More specific SMARTS expressions performed better for FOMS, but not VAMS for ER-a inhibitors (cite Table). For FOMS, the best fragment selection included pre-alignment to a phenolic SMARTS expression, which would align to the region that could form the interactions with Glu353 and Arg394. For this reason, it makes sense that this SMARTS expression and pre-alignment would produce the best performance for an ER-a inhibitor. (Explanation of why VAMS had better performance with lower specificity)
