Please note that this repository is constantly updated. You can retrieve the repository state for the published KinFragLib paper in release v1.0.0.
This repository holds the following resources:
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Fragment library data and a link to the combinatorial library data.
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Quick start notebook explaining how to load and use the fragment library.
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Notebooks
3.1. Notebooks covering the full analyses regarding the fragment and combinatorial libraries as described in the corresponding paper.
3.2. WIP: Notebooks providing a custom filtering framework to reduce the fragment library size.
Please find detailed description of files in data/ and notebooks/ in the folders' README files.
Exploring the kinase inhibitor space using subpocket-focused fragmentation and recombination
Protein kinases play a crucial role in many cell signaling processes, making them one of the most important families of drug targets. Fragment-based drug design has proven useful as one approach to develop novel kinase inhibitors. Usually, fragment-based methods follow a knowledge-driven approach, i.e., optimizing a focused set of fragments into molecular hits.
We present here KinFragLib, a data-driven kinase-focused fragment library based on the structural kinome data retrieved from the KLIFS database. Each kinase binding pocket (for DFG-in structures with non-covalent ligands) is automatically divided in KinFragLib into six subpockets, i.e. the adenine pocket (AP), front pocket (FP), solvent-exposed pocket (SE), gate area (GA) as well as back pocket 1 and 2 (B1 and B2), based on defined pocket-spanning residues. Each co-crystallized ligand is fragmented using the BRICS algorithm and its fragments are assigned to the respective subpocket they occupy. Following this approach, a fragment library is created with respective subpocket pools. This fragment library enables an in-depth analysis of the chemical space of known kinase inhibitors, and can be used to enumerate recombined fragments in order to generate novel potential inhibitors.
WIP: Custom KinFragLib provides a pipeline to filter the fragments in KinFragLib checking for unwanted substructures (PAINS and Brenk et al.), lead-/drug-likeness (Rule of Three and QED), synthesizability (similarity to buyable building blocks and SYBA) and pairwise retrosynthesizability. Each filter can be (de-)activated and the parameters can be modified by the user to create a customized filtered fragment library.
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Clone this repository.
git clone https://github.com/volkamerlab/KinFragLib.git
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Create the
kinfraglibconda environment.# Change to KinFragLib directory cd /path/to/KinFragLib # Create and activate environment conda env create -f environment.yml conda activate kinfraglib # Install the kinfraglib pip package cd .. pip install -e KinFragLib
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Open the notebook
quick_start.ipynbfor an introduction on how to load and use the fragment library.# Change to KinFragLib directory (if you have not already) cd /path/to/KinFragLib # Start jupyter lab to explore the notebooks jupyter lab
Please contact us if you have questions or suggestions.
- Open an issue on our GitHub repository: https://github.com/volkamerlab/KinFragLib/issues
- Or send us an email: [email protected]
We are looking forward to hearing from you!
This resource is licensed under the MIT license, a permissive open source license.
Sydow, D., Schmiel, P., Mortier, J., and Volkamer, A. KinFragLib: Exploring the Kinase Inhibitor Space Using Subpocket-Focused Fragmentation and Recombination. J. Chem. Inf. Model. 2020. https://pubs.acs.org/doi/abs/10.1021/acs.jcim.0c00839
@article{doi:10.1021/acs.jcim.0c00839,
author = {Sydow, Dominique and Schmiel, Paula and Mortier, Jérémie and Volkamer, Andrea},
title = {KinFragLib: Exploring the Kinase Inhibitor Space Using Subpocket-Focused Fragmentation and Recombination},
journal = {Journal of Chemical Information and Modeling},
volume = {60},
number = {12},
pages = {6081-6094},
year = {2020},
doi = {10.1021/acs.jcim.0c00839},
note ={PMID: 33155465},
URL = {https://doi.org/10.1021/acs.jcim.0c00839}
}