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26th March 2017 @ 07:38

Small tweak in the weighting of the scoring function. Increase weighting of molecules that are similar to the reference (highest affinity) ligand.

 

OSM-S363, 5.8

OSM-S364, 6.3

OSM-S365, 6.4 

OSM-S368, 5.6

OSM-S369, 5.6

OSM-S370, 6.0

OSM-S371, 6.0

OSM-S372, 5.6

OSM-S373, 5.8

OSM-S374, 5.8

OSM-S375, 6.3

23rd January 2017 @ 01:03

Now including Test Set B as training data.

 

Results with Prediction Set (Test Set C), pEC

OSM-S363, 5.9

OSM-S364, 6.6 

OSM-S365, 6.6 

OSM-S368, 6.1

OSM-S369, 5.7

OSM-S370, 6.2

OSM-S371, 6.2

OSM-S372, 6.0

OSM-S373, 5.7

OSM-S374, 5.7

OSM-S375, 6.6

 

Summary: Most promising are still OSM-S364, OSM-S365, OSM-S375. These predictions give fewer compounds with low pEC50 values than previous.

22nd January 2017 @ 23:52

QSAR modeling gives R2=0.68 for training set. Cross validation and test sets fit modestly. Fit is particularly poor at the high pEC range (>7), which is of highest interest. At this range, predicted pEC tends to underpredict experimental pEC. Should still be useful for ranking compounds.

Results with Prediction Set (Test Set C), pEC

OSM-S363, 5.9

OSM-S364, 6.5.  LHS: Sulfinyl unfavorable, hydroxyl favorable, benzyl is good modification candidate. 

OSM-S365, 6.6.  LHS: Sulfonyl unfavorable, hydroxyl favorable, benzyl is good modification candidate. 

OSM-S368, 5.4.   Shorter LHS less favorable.

OSM-S369, 5.7

OSM-S370, 6.2

OSM-S371, 6.0

OSM-S372, 5.5

OSM-S373, 5.8

OSM-S374, 5.8

OSM-S375, 6.4.  LHS: Hydroxyl favorable. RHS: Space can accomodate cubane though not necessarily favorable. Room to expand end of RHS.

 

Summary: Most promising are OSM-S365, OSM-S364, OSM-S375.

22nd January 2017 @ 08:53

Used Cresset Forge to generate conformers and align with docking model of highly potent compounds, MMV670947, bound to homology model of PfATPase, pose #5, as described in my other notebook. That pose was used as the "Reference" for Forge. 3D alignments are generated with training set composed of Series 4 compounds, excluding those marked as Test Sets B and C, and those with log potency <= 5. The low potency compounds were excluded because assays did not provide precise values, only marking them "< 5", for example. Test Set C was used as the "Prediction Set" by Forge.

Attached file contains ligand alignments.

Attached Files
22nd January 2017 @ 08:47

Made with JChem for Excel

Attached Files