FFF_Template

To use this repository:

1. Use this template to create a new repository
2. Clone the newly repository on IRIS
3. Follow the steps indicated below

1. Dependencies

Skip this section if you have run a FFF campaign with this template before

Pre-requisites

• SSH access to STFC/IRIS
• Working directory in cepheus-slurm:/opt/xchem-fragalysis-2/
• Conda setup w/ python >= 3.10
• Start a Jupyter notebook server in a SLURM job
• Set up BulkDock
• Install dev branch of HIPPO
• Install Fragmenstein
• Install FragmentKnitwork (optional, on a VM with a fragment network graph database)
• Install syndirella
• Install RichQueue
• Install PoseButcher (optional, useful if you have many subsites)

Checklist

• you can ssh to IRIS (cepheus-slurm.diamond.ac.uk)
• you can source a file to set up conda (e.g. create a bashrc_slurm.sh)
• you can connect to a Jupyter notebook on IRIS
• you can run python -m bulkdock status from the BulkDock directory
• you can import hippo from a notebook
• you can run fragmenstein --help
• you can ssh to the sw-graph VM (optional, only for Knitwork)
• you can run syndirella --help

2. Setup

• Define merging opportunities by creating tags of LHS hits in Fragalysis
• Download target from Fragalysis and place the .zip archive in the repo
• Setup target in BulkDock

cd $BULK
python -m bulkdock extract TARGET_NAME
python -m bulkdock setup TARGET_NAME

• Copy the aligned_files directory from $BULK/TARGETS/TARGET_NAME/aligned_files into this repository

3. Compound Design

• run the notebook hippo/1_merge_prep.ipynb

Fragmenstein

For each merging hypothesis

• go to the fragmenstein subdirectory cd fragmenstein
• queue fragmenstein job

sb.sh --job-name "fragmenstein" $HOME2/slurm/run_bash_with_conda.sh run_fragmenstein.sh HYPOTHESIS_NICKNAME

This will create outputs in the chosen HYPOTHESIS_NICKNAME subdirectory:

• HYPOTHESIS_NICKNAME_fstein_bulkdock_input.csv: use this for BulkDock placement

• output: fragmenstein merge poses in subdirectories

• output.sdf: fragmenstein merge ligand conformers

• output.csv: fragmenstein merge metadata

• placement with bulkdock

cp -v HYPOTHESIS_NICKNAME/HYPOTHESIS_NICKNAME_fstein_bulkdock_input.csv $BULK/INPUTS/TARGET_HYPOTHESIS_NICKNAME_fstein.csv
cd $BULK
python -m bulkdock place TARGET_NAME INPUTS/TARGET_HYPOTHESIS_NICKNAME_fstein.csv

• monitor placements (until complete)

python -m bulkdock status

• export Fragalysis SDF

sb.sh --job-name "bulkdock_out" $HOME2/slurm/run_python.sh -m bulkdock to-fragalysis TARGET OUTPUTS/SDF_FILE METHOD_NAME

Fragment Knitwork

Running Fragment Knitting currently requires access to a specific VM known as graph-sw-2. If you don't have access, skip this section

• git add, commit and push the contents of aligned_files and knitwork to the repository
• git clone the repository on graph-sw-2
• navigate to the knitwork subdirectory

Then, for each merging hypothesis:

• Run the "fragment" step of FragmentKnitwork: ./run_fragment.sh HYPOTHESIS_NICKNAME
• Run the pure "knitting" step of FragmentKnitwork: ./run_knitwork_pure.sh HYPOTHESIS_NICKNAME
• Run the impure "knitting" step of FragmentKnitwork: ./run_knitwork_impure.sh HYPOTHESIS_NICKNAME
• Create the BulkDock inputs: python to_bulkdock.py HYPOTHESIS_NICKNAME
• git add, commit and push the CSVs created by the previous step
• back on cepheus-slurm pull the latest changes
• Run BulkDock placement as for Fragmenstein above

cp -v HYPOTHESIS_NICKNAME/HYPOTHESIS_NICKNAME_knitwork_pure.csv $BULK/INPUTS/TARGET_HYPOTHESIS_NICKNAME_knitwork_pure.csv
cp -v HYPOTHESIS_NICKNAME/HYPOTHESIS_NICKNAME_knitwork_impure.csv $BULK/INPUTS/TARGET_HYPOTHESIS_NICKNAME_knitwork_impure.csv
cd $BULK
python -m bulkdock place TARGET_NAME INPUTS/TARGET_HYPOTHESIS_NICKNAME_knitwork_pure.csv
python -m bulkdock place TARGET_NAME INPUTS/TARGET_HYPOTHESIS_NICKNAME_knitwork_impure.csv

• Export Fragalysis SDF as for Fragmenstein

4. Scaffold selection

Syndirella retrosynthesis

Review chemistry

HIPPO filtering

Fragalysis curation

5. Syndirella elaboration

6. HIPPO

Load elaborations

Quote reactants

Solve routes

Calculate interactions

Generate random recipes

Score random recipes

Optimise best recipes

Create proposal web page

7. Review & order

Review chemistry

Order reactants