Heba Cyclic Structure Scoring?

[mattodd]

Hi @TomkUCL @edwintse @jemimahaque - do we have some synthetically accessible versions of the cyclic compound @H-agha had been pursuing (https://github.com/StructuralGenomicsConsortium/CNP4-Nsp13-C-terminus-B/issues/2#issuecomment-988953912)? We should minimise and dock and see if any of them should be pursued. We'll discuss this next Friday, so docking before then (i.e. sending to Konstantin ASAP) would be useful.

[jemimahaque]

Here are a couple of SMILES:

CN1C=C(NC(C2=C3C=CC=C2)=O)C(C4=CNN=C4CC3)=N1

CN1C=C(NC(C2=C3C=CC=C2)=O)C(CC4=CNN=C4C3)=N1

CN1C=C(NC(C2=C3C=CC=C2)=O)C(C4NCCN4CC3)=N1

CN1C=C(NC(C2=C3C=CC=C2)=O)C(CC4=CC3=NN4)=N1

CN1C=C(NC(C2=C3C=CC=C2)=O)C(CC4=C(CC)C(CC)=C3N4)=N1

CN1C=C(NC(C2=C3C=CC=C2)=O)C(CC4=NC3=NO4)=N1

CN1C=C(NC(C2=C3C=CC=C2)=O)C(CC4=NN=C3O4)=N1

O=C1NC2=NN(CC3=CC=CC(O)=C3)C=C2CC4=CC=CN4CCC5=C1C=C(C6=CC=CO6)C=C5

O=C1NC2=NN(CC3=CC=CC(O)=C3)C=C2CC4=CC=CN4CCC5=C1C=C(C6=CC=CC(O)=C6)C=C5

CN1C=C(C(C2=CNN=C2CC3)=N1)NC(C4=C3C=CC(C5=CC=CO5)=C4)=O

O=C(C1=C2C=CC(C3=CC=CO3)=C1)NC(C(CC4=CN(CC5=CC=C(O)C=C5)N=C4C2)=N6)=CN6CCCO

More to be added throughout today

[H-agha]

Hi @TomkUCL @jemimahaque. Here are the glide scores for two compounds Tom proposed earlier and 18 compounds were proposed by Jemima. Jemima compounds 1-18 + Tom T3-7 &8.pptx

A clarification: compounds J1-7 are the same compounds as J8-14.

[jemimahaque]

Hi @TomkUCL @jemimahaque. Here are the glide scores for two compounds Tom proposed earlier and 18 compounds were proposed by Jemima. Jemima compounds 1-18 + Tom T3-7 &8.pptx

Thank you Heba @H-agha, it seems like the compound J4/J11 has the best glide score - I will come up with a couple of structures now to optimise it further.

Optimised SMILES:

@H-agha

J19 = O=C(C1=C2C=CC(C3=CC=CO3)=C1)NC(C(CC4=CC2=NN4)=N5)=CN5CC6=CC=CC(O)=C6

J20 = O=C(C1=C2C=CC=C1)NC(C(CC3=CC2=NN3)=N4)=CN4CC5=CC=CC(O)=C5

J21 = O=C(C1=C2C=CC(C3=CC=CO3)=C1)NC(C(CC4=CC2=NN4)=N5)=CN5CC6=CC=CC(O)=C6

J22 = O=C(C1=C2C=CC=C1)NC(C(CC3=CC2=NN3)=N4)=CN4CN5CCOCC5

J23 = O=C(NC1=CN(CC2=CC=CC(C(F)(F)F)=C2)N=C1CC3=CC4=NN3)C5=C4C=CC(C6=CC=CO6)=C5

J24 = O=C(NC1=CN(CC2=CC=CC(O)=C2)N=C1CC3=CC4=NN3CC5=CC=C(C(F)(F)F)C=C5)C6=C4C=CC(C7=CC=CO7)=C6

J25 = O=C(NC1=CN(CC2=CC=CC(OC3=CC=CC=C3)=C2)N=C1CC4=CC5=NN4)C6=C5C=CC(C7=CC=CO7)=C6

[H-agha]

Hi @TomkUCL @jemimahaque. Here are the glide scores for two compounds Tom proposed earlier and 18 compounds were proposed by Jemima. Jemima compounds 1-18 + Tom T3-7 &8.pptx

Thank you Heba @H-agha, it seems like the compound J4/J11 has the best glide score - I will come up with a couple of structures now to optimise it further.

Optimised SMILES:

O=C(C1=C2C=CC(C3=CC=CO3)=C1)NC(C(CC4=CC2=NN4)=N5)=CN5CC6=CC=CC(O)=C6

Keep working in your optimization. J19 score is -5.214

[mattodd]

Yes, keep going! What are we, kind of, aiming for as a score?

[jemimahaque]

Also, how large can these fragments be at this stage?

[H-agha]

Yes, keep going! What are we, kind of, aiming for as a score?

Most of the previous compounds even the non cyclic ones were in the range of -3 to -4. In this series, this is the first time to get a score of -5. I think we can try to aim as high score as we can such as -10.

[H-agha]

@jemimahaque. Here are the score for compounds J19-J25.

optimized J series- J19-25.pptx

Here is the pymol session to check the space around the compounds Jemima 19-23- pymol .pse.zip

[jemimahaque]

@jemimahaque. Here are the score for compounds J19-J25.

optimized J series- J19-25.pptx

Here is the pymol session to check the space around the compounds Jemima 19-23- pymol .pse.zip

Thank you!

[jemimahaque]

Here is the reference for making the pyrazole linker in these structures

DOI: 10.1002/chem.200701769

[jemimahaque]

Hi @H-agha, would you be able to upload the slides from today's meeting please?

[H-agha]

Hi @jemimahaque, here are the slides of the new scaffold? cyclic structure new scaffold.pptx

[TomkUCL]

Thanks Heba, really nice.