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StructuralGenomicsConsortium / CNP14-WDR91

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FEP modelling #9

Open KangpingL opened 4 months ago

KangpingL commented 4 months ago 
          > We could use some more quantitative analysis of binding free energy, like FEP (free energy perturbation). Will take a look in a few days when I have more time.

Hi, I agree. Our collaborators have done some FEP calculations previously. They first validated the method against known actives and inactives and the predicted activity (scores) generally matched the experimental KD trend. They then ran it on 20 unpredicted molecules image and their experimental results 2 1

It's quite interesting that the origin of KD=0.67 uM molecule is actually a dummy generated by FEP for transition between 2 "dissimilar" molecules

I will create a new issue for any update/ discussion of FEP to make this issue tidy and easier to read.

Originally posted by @KangpingL in https://github.com/StructuralGenomicsConsortium/CNP14-WDR91/issues/6#issuecomment-1980710374

sherifelsabbagh commented 4 months ago

Okay interesting..

So I took the compound with the high FEP energy score (-8.2 kcal/mol). It shows docking score of -7.5 (hit was -7.4).

Concerning the interactions, it formed two hydrophobic interactions with LEU477 (instead of one) and lost the hydrogen bond with ARG.

image

mattodd commented 3 months ago

OK @sherifelsabbagh does this structural model reveal anything new we can do to the molecule to pick up a potentially unused interaction with the protein? Any pocket we can grow into? Any polar residue lacking a bond?

sherifelsabbagh commented 3 months ago

Unfortunately I lost the data on my laptop so I need to redo the modeling experiments... I will tell you once I do it..

KangpingL commented 2 months ago

2nd round of FEP results thanking to contributions from Prof. Matthieu Schapira and Dr. Conrad Veranso: WDR91_Second_run_FEP2.pptx

Computational results aligns well with experimental data (#5)

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Sulfone-dihalogen analogues were predicted to be better than those mentioned at the beginning of this issue.

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sherifelsabbagh commented 2 months ago

2nd round of FEP results thanking to contributions from Prof. Matthieu Schapira and Dr. Conrad Veranso: WDR91_Second_run_FEP2.pptx Computational results aligns well with experimental data (#5) Sulfone-dihalogen analogues were predicted to be better than those mentioned at the beginning of this issue.

interesting... may be model these compounds by docking to see how they interact ?