Question Regarding the Preparation of xyz Files for DiffPROTACs input

[innaka2020]

Hello,

I am trying to use DiffPROTACs, but I encountered difficulties while preparing the input xyz files. I have two molecules, one serving as the warhead and the other as the E3 ligase ligand. I want to create a linker between them.

Would you give some advice on handling the warhead and the E3 ligase ligand in this process? When I tried to generate 3D coordinates using LigPrep from the SMILES of the warhead and E3 ligase ligand, I faced the following issues:

1. I would like to know how to connect the two molecules (warhead and E3 ligase ligand) before inputting them into LigPrep.
2. LigPrep generates multiple 3D conformations. Is there any specific criterion for selecting the appropriate conformation, or parameters for LigPrep?

I would appreciate your response.

Best regards,

[Fenglei104]

Hi,

Sorry, actually I am not a specialist at this. My lab-mate helps me. And I am a little confused about your question. But I would like to share you something what I have done.

1. I am not sure why you want to connect the two ligands. I put the whole PROTAC into the LigPrep, and then divided them into ligands and linker. If you do not have the PROTAC molecules, you can find some similar PROTACs in RCSB and just align the two ligands to that PROTACs without LigPrep.
2. For simplicity, I just use the random conformation. If you want more accurate results, you can use the similar PROTACs with existing crystal structure and then do the alignment. Further you can do the energy minimization. Or you can do the docking, and select the ones with lower energy.

I hope it helps.

[innaka2020]

First of all, thank you for your response.

Regarding Question 1, I have some pairs of warheads and E3 ligands (all of them are represented in SMILES), and want to generate PROTACs using DiffPROTACs. In this case, what kind of processing should be performed to create the input file for DiffPROTACs (in xyz format)? Could you please let me know the processing steps that produce the input file for this case?
I would appreciate your response.

Regardly