Deep Docking – Accelerate Virtual Screening by 50X

Deep docking (DD) is a deep learning-based tool developed to accelerate docking-based virtual screening. In this repository you can find all what you need to screen ultra-large chemical libraries such as ZINC15 database (containing >1.3 billion molecules) using your favourite docking program. For further information please refer to our paper. The dataset used for building the models reported in the paper can be found at this link.

About this repository

The pd_python folder contains all the scripts that you need to run DD. Copy the folder to your machine prior to start. The slurm folder contains some examples of scripts to automate DD on clusters using slurm queueing system. The temp folder contains templates and examples of files that need to be created for running DD.

Prerequisites

To run DD you need to install the following packages:

• Package installer for python (pip)
• Anaconda
• A program to create 3D conformations from SMILES
• Docking program

Then you need to set up the following virtual environments:

• Python3 virtual environment. Install rdkit

• Activate the rdkit conda environment if not already activated

      conda activate environment_name
  

• Install Wget package (to download the smiles for later)

      pip install wget
  

• Python3 virtual environment (different from previous one).

      virtualenv -p python3 tensorflow_gpu 
  

• Activate the virtual environment

      source /path/to/tensorflow_gpu/bin/activate
  

• Install tensorflow-gpu, pandas, numpy, keras, matplotlib and sklearn

      pip install -r requirements.txt
  

Preparing molecules for DD

To run the code you need to download the SMILES of the molecules and calculate their Morgan fingerprint with size of 1024 bits and radius of 2 as QSAR descriptors.

DOWNLOAD AND PREPARE SMILES

• You can skip the next three points if you have already the database in SMILES format, or if you want to use a different database than ZINC15

• Go here and download the 2D SMILES (.smi) in url format

• Activate the virtual environment where rdkit was installed

• Run

      python download_zinc15.py -up path_url_file/url_file -fp path_smile_folder -fn smile_folder -tp num_cpus
  

  This will create a path_to_smile_folder/smile_folder folder and download the SMILES within it. This step can take few hours, and ~84GB memory for 1.36 billion molecules.

• Reorganize the SMILES files into a number of evenly populated files equal to the number of CPUs used for phase 1 (see below). Activate the tensorflow environment and run

      python smile_simplification.py -sfp path_smile_folder/smile_folder -tp num_cpus -tn final_number_of_files
  

CALCULATION OF MORGAN FINGERPRINTS

• Activate the rdkit environment

• Run the following command

      python Morgan_fing.py -sfp path_smile_folder/smile_folder -fp path_morgan_folder -fn morgan_folder -tp num_cpus
  

  This will create a path_to_morgan_folder/morgan_folder folder, and generate the Morgan fingerprints of 1024 bits of size and radius of 2 within it. It is recommended as many CPUs as possible to speed up the process. This step takes ~260GB memory for 1.36 billion molecules

Run DD

Create the project

Before starting DD, create a project folder and create a text file named "logs.txt" within it, following this format. Lines in the logs file are:

Line number	Value	Explanation
1	path_project_folder	Path to the project folder
2	project_folder	Name of project folder
3	path_grid_file/grid_file	Path and name of docking grid file; write a random line if you do not use a grid
4	path_morgan_folder/morgan_folder	Path to files containing the previously calculated QSAR descriptors (Morgan fingerprints)
5	path_smile_folder/smile_folder	Path to files containing SMILES of molecules
6	path_3dsdf_folder/3dsdf_folder	Path to precalculated 3D sdf conformations of molecules; write a random line if you do not have them
7	number_of_molecules_to_sample	Number of molecules sampled at each iteration. In the first iteration, this number of molecules will be split in three to form initial training, validation and testing, from the second iteration it will be the number of molecules added to the training set

DD pipeline is divided in 5 sequential phases to be repeated over multiple iterations until a desired number of final predicted virtual hits is reached:

Phase 1. Random sampling of molecules

1. The number of molecules to be sampled is defined in the logs.txt file and can be modified any time during the runs (for example, to keep constant the number of molecules added to the training set between iteration 1 and the other iterations). Choose the number according with the computational resources that are available (for the paper we sampled 3 million molecules for iteration 1 (so that can be divided into 1 million each for training, validation and test) and 1 million from iteration 2 onwards, all for training), as these molecules will be docked later on. During iteration 1 this sample of molecules will be splitted in three to build initial training, validation and test set. From iteration 2 it will correspond to the number of molecules that are used for augmenting the training set (so do not worry about the naming convention from iteration 2 onwards).

2. Run phase 1

      bash pd_python/phase_1.sh iteration_no n_cpus path_to_log_file path_tensorflow_venv
   

3. This step will create few folders and files inside the iteration folder relative to your current iteration. First, it will create three txt files containing the names of molecules that were randomly sampled. Note that the name of these files will always start with train, valid and test, even after iteration 1 (when molecules are added only to the training set). Then, a morgan folder will be generated, containing three csv files with Morgan fingerprints for the sampled molecules. Finally, phase 1 will generate three smi files in a smile folder, with the SMILES of the sampled molecules, to be used as input for docking (phase 2).

Phase 2. Prepare molecules for docking
Convert SMILES from phase 1 to 3D sdf format for docking (if it is not done internally by the docking software). This step includes assigning tautomer and protonation states and generating conformers, and can be done with different free (e.g. openbabel) or licensed programs (e.g. omega).

Phase 3. Molecular docking

1. Run docking using the created sdf files
2. From the docking results create three csv files with two columns, ZINC_ID, r_i_docking_score (use these exact headings):
   • Populate the ZINC_ID column with the IDs of molecules (use the same heading even if you are not screening ZINC)
   • Add the corresponding scores in the r_i_docking_score column
3. Name the csv files as training_labels.txt, validation_labels.txt, testing_labels.txt, according with to the original smi file used to create files for docking. Follow this format
4. Put these files in the iteration_no folder

Phase 4. Neural network training

1. Training neural network models with different sets of hyperparameters (12 combinations of hyperparameter values will be evaluated). Activate the tensorflow environment and run

      python simple_job_models_noslurm.py -n_it iteration_no -mdd path_morgan_folder/morgan_folder -time training_time -protein project_folder_name -file_path path_to_project_folder -pdfp path_to_pd_python/pd_python -tfp path_tensorflow_venv -min_last minimum_molecules_at_last_iteration
   

2. Training time should be set between 1 and 2 (hours)

3. The minimum_molecules_at_last_iteration defines the number of top scoring molecules considered as virtual hits in the validation set during the last iteration. For example, setting this value to 100 for a validation set of 1 million molecules corresponds to consider the top 0.01% molecules as virtual hits, and so on. Default value is 200.

4. Execute all the bash scripts in path_project_folder/project_folder/iteration_no/simple_job

Phase 5. Selection of best model and prediction of the entire database

1. For chosing the best model run

      python hyperparameter_result_evaluation.py -n_it iteration_no -protein project_folder_name -file_path path_project_folder -mdd path_morgan_folder/morgan_folder
   

2. Generate bash files for prediction:

      python simple_job_predictions_noslurm.py -protein project_folder_name -file_path path_project_folder -n_it iteration_no -mdd path_morgan_folder/morgan_folder
   

3. Execute all the bash scripts in path_project_folder/project_folder/iteration_no/simple_job_predictions

4. To check the number of molecules that are left after each iteration, sum the last column of the passed_file_ct.txt created in path_project_folder/project_folder/iteration_no/morgan_1024_predictions. You can compare this number with the number of left molecules predicted from the test set (total_pred_left) in path_project_folder/project_folder/iteration_no/best_model_stats.txt, and verify whether they are close.

Repeat the above phases 1-5 for as many iterations as needed to reach a desired number of left molecules. You will just need to change the iteration_no value every time you start from phase 1 again (sometimes the number of molecules will plateu after a point i.e. the decrease will become very small after each iteration, at that point you can use the useful tip mentioned below).

After DD

After the final iteration is completed, the final set can be directly docked to remove residual low scoring molecules. Some molecules could have been randomly sampled and docked during the previous iterations, and therefore do not need to be docked again:

• Run

      bash final_phase_noslurm.sh iteration_no number_of_cpus path_logs_file path_tensorflow_venv
  

  This will create a new folder in the project called after_iteration and put all the molecules that have been already docked inside the docked folder within it, and all the remaining SMILES in the to_dock folder

• You can dock the SMILES using the same procedure as step 2 and 3

Useful tips

You can select a subset of top predicted virtual hits instead of all of them to dock after the final iteration, using the rank provided by the model probabilities of being virtual hits (for example you completed 3 iterations after which 30 million molecules are remaining, and you want to dock only the top 10 million compounds). Run

      python Prediction_morgan_1024_top_n.py -protein protein_name -it iteration_no -file_path path_to_protein -top_n top_n_molecules

Executing this command will rename the original morgan_1024_predictions folder to morgan_1024_predictions_old, and create a new morgan_1024_predictions folder inside iteration_no, with all the files generated by phase 5 for the top n compounds only.