ssBind: Sub-Structure-based alternative BINDing modes generator for protein-ligand systems

ssBind offers different methods for generating multiple conformations by restraining certain sub-structures. This feature enables researchers to systematically explore the effects of various substituents attached to a common scaffold on the binding and to refine the interaction patterns between ligand molecules and their protein targets.

Available methods for conformer generation

Random conformer generation with RDKit
Dihedral angle sampling
PLANTS docking tool
rDock docking tool

Minimization and Scoring Options

Scoring and minimization with AutoDock Vina or smina
Overall minimization using gromacs with GAFF, CGenFF and OpenFF

Installation (from source)

$ git clone https://github.com/suleymanselim/ssBind
$ cd ssBind
$ pip install .

Examples using the command line scripts

1. Random conformational sampling using RDKit

run_ssBind.py --reference reference.mol2 --ligand ligand.mol2 --receptor receptor.pdb --generator rdkit

2. Using dihedral angles to generate conformers

run_ssBind.py --reference reference.mol2 --ligand ligand.mol2 --receptor receptor.pdb --generator angle

3. Generating conformers using PLANTS docking tool

PLANTS allows the restraint of the position of a ring system or a single non-ring atom in docking. In this case, all the fixed scaffold's translational and rotational degrees of freedom are completely neglected. The code automatically determines the ring system to be fixed in the reference scaffold. If there is no ring system in the reference, only the specific atom is restrained.

run_ssBind.py --reference reference.mol2 --ligand ligand.mol2 --receptor receptor.pdb --generator plants

Some side-chains can also be treated flexibly with PLANTS.

## A subset of the sidechains around the ligand within 5 Å in the binding pocket will be allowed to move.
run_ssBind.py --reference reference.mol2 --ligand ligand.mol2 --receptor receptor.pdb --generator plants --flexDist 5

## You can also determine the flexible sidechains
run_ssBind.py --reference reference.mol2 --ligand ligand.mol2 --receptor receptor.pdb --generator plants --flexList "MET49,MET165"

4. Tethered scaffold docking with rDock

In tethered scaffold docking, the ligand position is constrained, ensuring they align with the substructure coordinates of a reference ligand. This involves overlaying a ligand with a corresponding substructure onto the coordinates of the reference substructure. The ligand's degrees of freedom are anchored to their predefined reference position. rDock facilitates this by offering the flexibility to separately adjust the ligand's position, orientation, and dihedral angles.

run_ssBind.py --reference reference.mol2 --ligand ligand.mol2 --receptor receptor.pdb --generator rdock

Python tutorial

1. Generating conformers using PLANTS

from ssBind import SSBIND
from ssBind.chem_tools import MolFromInput

## Input files
reference_substructure = MolFromInput('reference.mol2')
query_molecule = MolFromInput('ligand.mol2')
receptor_file = 'receptor.pdb'

ssbind = SSBIND(reference_substructure = reference_substructure, query_molecule =query_molecule, receptor_file = receptor_file)

## PLANTS generates many conformers 'conformers.sdf' and their scores 'Scores.csv'
ssbind.generate_conformers_plants()

## Clustering identifies some binding modes based on binding scores and PCA.
ssbind.clustering(conformers = 'conformers.sdf', scores = 'Scores.csv')