Tutorial

This is the tutorial page for the MORLD web service.
Follow the tutorial step by step.

Demo
Queue Page
Result Files
Potential Error Types

Demo

In this tutorial, we will optimize the compound, ponatinib, to generate novel inhibitors against the target protein, DD1 kinase. You can download the prepared pdb file of DDR1 kinase here.

According to Autodock Vina, Ponatinib shows the binding energy around -13.1 kcal/mol against DDR1. Using MORLD, We will decrease the binding energy of the initial molecule, ponatinib, against DDR1.

If you want to check the result of demo quickly, please refer to the JobID #1 at Queue page.

Step 1
To submit the job, go to "Job Submission" page.

Step 2
Insert the job name. For example, demo_pona

(Optional) If you want to be notified of job termination, enter your email at "Email" field.

(Optional) If you want to secure your job, enter the password at "Password" field. The result file will be secured by 7z format with the password.

Step 3
Insert the canonical SMILES string of ponatinib at the text field of "Initial molecule".

CC1=C(C=C(C=C1)C(=O)NC2=CC(=C(C=C2)CN3CCN(CC3)C)C(F)(F)F)C#CC4=CN=C5N4N=CC=C5

Step 4
Upload the prepared pdb file of the target protein, DDR1 3zosA_prepared.pdb.

To prepare a PDB file for MORLD, remove all water molecules, and ligands in the PDB structure. Also, the protein needs protonation for accurate docking. Use protonation programs like PDB2PQR server.

Step 5
(Optional) You can modify the parameter of MORLD model at "Modification Configuration". You can pass this step with the default setting.

Atom types: You can customize the atom types for modification. The atom types should be the atomic symbols as like ones in SMILES string. Select the atom types by check boxes or enter your own atom types with "," delimiter. A default value is set to C, O, N.

Max num. of modification: MORLD will add or remove atoms by this given number. You can set the number of modifying action at each episode. The larger value will allow to modify the initial molecule more differently. On the other hand, small value will produce similar structure with the inital one.

Num. of training episode: MORLD will generate optimized molecules by this given number. *If an error occurs during the docking process, the number of molecules generated may be small than this number.The higher the number, the more experience of modification that MORLD gains and, consequently, the more likely to get better results. Usually, at least 5000 episodes are need to get moderate results.

Weight for SA score: You can customize a weight value for synthetic accessibility (SA) score. The default value is set to 1 but you can change to 0 (not consider SA score) or larger than 1 (more focus on SA score).

Weight for QED score: You can customize a weight value for quntitative estimate of drug-likeness (QED) score. The default value is set to 1 but you can change to 0 (not consider QED score) or larger than 1 (more focus on QED score).

Step 6
Insert the binding site information. The given values are derived from PDB ID:3ZOS and ADT (AutoDockTools).

Center x: -7.5
Center y: 2.5
Center z: -40
Size x: 24
Size y: 20
Size z: 20

Step 7
Click the "Submit" button and check the job has been submitted at "Queue" page.

With the default setting, it will takes about two days. If you want to run a test trial, reduce the parameter "Max num. of modification" or "Num. of training episode".

Queue Page

Check the submitted job at "Queue" page.

Job ID
ID number of the submitted job.

Status
waiting: The job has been successfully submitted and is waiting in the queue to be prepared for execution.

prepared: The system has created a directory for the job and moved the necessary files. The job is now fully prepared and will start as soon as computing resources become available.

running: The job is successfully running on the server.

finished: The job is finished and you can download the result file.

failed: The job is stopped by error. Please check the input information whether it is entered correctly.

Job
Name
The name of job submitted.

Submitted
Time
Submitted time of the job.

Donwload
Link
If the job has finished successfully, then the Download link of the result will appear.

Result Files

Inside the download file, you will find below files and folder.

optimized_
total.csv
This files contains all the optimized molecules. The number of optimized molecules are the same as the number of training episode. If you set the number of training episode as 5000, then there are 5000 optimized molecules in "optimized_total.txt" file.

Each column represents the generated number, SMILES code of the generated molecule, binding energy (Qvina score), SA score, and QED score respectively. With this data, you can sort by the binding energy to find the highest binding affinity molecule. Or set the minimum SA score to filter the irrational structure of the optimized molecules.

log_
run.txt
This file is a log of the MORLD model. It shows in what order the molecules are modified at each Episode.

docking_
pose/
This folder contains the files of binding pose of the optimized molecule. Each file is named as "pose_##.pdbqt" where ## is the generated number. You can see the binding pose of the highest docking score molecule in "optimized_total.txt" file by checking the generated number.

You can open .pdbqt file and see the binding pose with the target protein with visulization tool such as Pymol.

(job ID)_
info.txt
This file is contains the input paremeters of the job.

Potential Error Types

This is a guide on troubleshooting steps for when a job fails

Input smiles error
[Possible Error Messages]

"The SMILES string of your input molecule, your_input_SMILES, is invalid. Please check and enter a valid SMILES format file."

"The SMILES string of your input molecule, your_input_SMILES, cannot be converted to a PDBQT file format with openbabel. Please check your input molecule."

[Solutions]

Please check if the format of the SMILES you entered is correct, and verify whether it can be converted to a PDBQT file using OpenBabel.

OpenBabel 3D Structure Generation Error
[Possible Error Messages]

"Obabel timeout error: Stereochemistry is wrong, using the distance geometry method instead.

[Solutions]

This error occurs because OpenBabel encountered an error while generating a 3D structure from the SMILES. Please check the stereochemistry information in your input SMILES. If the stereochemistry information is not important, please try converting it to canonical SMILES format and input again.

Receptor Protein Error
[Possible Error Messages]

"The pdb file you uploaded cannot be converted into pdbqt file. Please check your pdb file."

[Solutions]

This error means that the input PDB file cannot be converted to a PDBQT file. Please verify that your PDB file is correct.

Docking Error
[Possible Error Messages]

"Cannot calculate docking scores. Please check your docking configurations; binding pocket size or location."

[Solutions]

This error occurs when QuickVina does not execute properly. While there are various causes for this error, you can check the followings:
1. Verify that the location of binding box is correctly set. Check if the coordinate values you entered match the pocket location in the receptor protein's PDB file.
2. Confirm that the binding box size is appropriate. Errors may occur if the binding box size is too large or too small. The search space volume should not exceed 27000 Angstrom^3.

Other Errors
In addition to the errors mentioned above, we are taking measures to address other errors that may occur. If you experience difficulties in resolving an issue, please contact the server manager, and we will provide assistance.

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