Merge pull request #67 from volkamerlab/dev

[v2.0.0] CustomKinFragLib release

.github/workflows/ci.yml

@@ -74,6 +74,6 @@ jobs:
       - name: Run tests
         shell: bash -l {0}
         run: |
-          PYTEST_ARGS="--nbval-lax --nbval-current-env --nbval-cell-timeout=1800"
-          pytest $PYTEST_ARGS
-
+          PYTEST_ARGS="--nbval-lax --nbval-current-env --nbval-cell-timeout=7200"
+          PYTEST_IGNORE="--ignore=notebooks/custom_kinfraglib/2_3_custom_filters_paper.ipynb"
+          pytest $PYTEST_ARGS $PYTEST_IGNORE

README.md

@@ -1,6 +1,6 @@
 # KinFragLib: Kinase-focused fragment library
 
-[![GitHub Actions Build Status](https://github.com/volkamerlab/KinFragLib/workflows/CI/badge.svg)](https://github.com/volkamerlab/KinFragLib/actions?query=workflow%3ACI)
+[![GitHub Actions Build Status](https://github.com/volkamerlab/KinFragLib/actions/workflows/ci.yml/badge.svg)](https://github.com/volkamerlab/KinFragLib/actions?query=branch%3Amaster+workflow%3ACI)
 
 ![KinFragLib workflow](./docs/img/toc_github_kinfraglib.png)
 
@@ -10,31 +10,36 @@ You can retrieve the repository state for the published KinFragLib paper in rele
 
 ## Table of contents
 
-- [Description](#description)
 - [Repository content](#repository-content)
+- [Description](#description)
 - [Quick start](#quick-start)
 - [Contact](#contact)
 - [License](#license)
 - [Citation](#citation)
+- [List of publications](#list-of-publications)
+
 
 ## Repository content
 
 This repository holds the following resources:  
 
 1. Fragment library data and a link to the combinatorial library data.
 2. *Quick start* notebook explaining how to load and use the fragment library.  
-3. Notebooks covering the full analyses regarding the fragment and combinatorial libraries as described in 
-the corresponding paper.  
+3. Notebooks 
+
+    3.1. *KinFragLib*: Notebooks covering the full analyses regarding the fragment and combinatorial libraries as described in 
+          the corresponding paper.  
+    3.2. *CustomKinFragLib*: 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.
+Please find detailed descriptions of files in `data/` and `notebooks/` in the folders' `README` files.
 
 ## Description
 
 **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. 
+Fragment-based drug design has proven useful as one approach to developing novel kinase inhibitors. 
 Usually, fragment-based methods follow a knowledge-driven approach, i.e., optimizing a focused set of fragments into 
 molecular hits. 
 
@@ -46,9 +51,11 @@ well as back pocket 1 and 2 (B1 and B2), based on defined pocket-spanning residu
 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 
+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.
 
+We have added an extension with *CustomKinFragLib* which provides a pipeline to filter the fragments in KinFragLib checking for unwanted substructures (PAINS and Brenk et al.), 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. 
+
 ## Quick start
 
 1. Clone this repository.
@@ -98,7 +105,7 @@ We are looking forward to hearing from you!
 
 ## License
 
-This resource is licensed under the [MIT](https://opensource.org/licenses/MIT) license, a permissive open source license.
+This resource is licensed under the [MIT](https://opensource.org/licenses/MIT) license, a permissive open-source license.
 
 ## Citation
 
@@ -146,5 +153,3 @@ Backenköhler M, Groß J, Wolf V, Volkamer A.
 - **Constructing Innovative Covalent and Noncovalent Compound Libraries: Insights from 3D Protein–Ligand Interactions** Xiaohe Xu, Weijie Han, Xiangzhen Ning, Chengdong Zang, Chengcheng Xu, Chen Zeng, Chengtao Pu, Yanmin Zhang, Yadong Chen, and Haichun Liu *Journal of Chemical Information and Modeling* **2024**[10.1021/acs.jcim.3c01689](https://pubs.acs.org/doi/10.1021/acs.jcim.3c01689)
 
 
-
-

data/README.md

@@ -9,3 +9,6 @@ Overview of data content:
 - `fragment_library_reduced/`: Reduced fragment library: Select a diverse set of fragments (per subpocket) for recombination starting from the filtered fragment library.
 - `combinatorial_library/`: Combinatorial library based on the reduced fragment library.
 - `external/`: Data from external resources.
+- `filters/`: Data used for custom filters.
+- `fragment_library_custom_filtered/`: Custom filtered fragment library: Pre-filtered (remove pool X,  deduplicate per subpocket, remove unfragmented ligands, remove all fragments that connect only to pool X), and filtered for unwanted substructures (PAINS and Brenk), drug-likeness (Ro3 and QED), synthesizability (buyable building blocks and SYBA) and pairwise retrosynthesizability (using ASKCOS).
+- `fragment_library_old/`: Full fragment library v1.1.0 which was described in the KinFragLib paper. 

data/combinatorial_library/README.md

@@ -9,13 +9,13 @@ In order to run the analysis notebooks, please download this dataset to this fol
 
 ## Raw data
 
-- `combinatorial_library.json`: Full combinatorial library, please refer to `notebooks/4_1_combinatorial_library_data_preparation.ipynb` at https://github.com/volkamerlab/KinFragLib for detailed information about this data format
+- `combinatorial_library.json`: Full combinatorial library, please refer to `notebooks/kinfraglib/4_1_combinatorial_library_data_preparation.ipynb` at https://github.com/volkamerlab/KinFragLib for detailed information about this data format
 - `combinatorial_library_deduplicated.json`: Deduplicated combinatorial library (based on InChIs)
 - `chembl_standardized_inchi.csv`: Standardized ChEMBL 33 molecules in the form of InChI strings.
 
 ## Processed data
 
-Data extracted from `combinatorial_library_deduplicated.json`, performed in `notebooks/4_1_combinatorial_library_data_preparation.ipynb` at https://github.com/volkamerlab/KinFragLib.
+Data extracted from `combinatorial_library_deduplicated.json`, performed in `notebooks/kinfraglib/4_1_combinatorial_library_data_preparation.ipynb` at https://github.com/volkamerlab/KinFragLib.
 
 - `n_atoms.csv`: Number of atoms for each recombined ligand
 - `ro5.csv`: Number of ligands that fulfill Lipinski's rule of five (Ro5) and its individual criteria; number of ligands in total

data/filters/Brenk/README.md

@@ -0,0 +1,3 @@
+# Brenk et al.
+
+- `unwanted_substructures.csv`: File with unwanted substructures provided by Brenk et al. [(Chem. Med. Chem. (2008), 3, 535-44)](https://chemistry-europe.onlinelibrary.wiley.com/doi/full/10.1002/cmdc.200700139) containing the name and the SMARTS string of the unwanted substructure.

data/filters/Brenk/unwanted_substructures.csv

@@ -0,0 +1,105 @@
+name smarts
+>2EsterGroups C(=O)O[C,H1].C(=O)O[C,H1].C(=O)O[C,H1]
+2-haloPyridine n1c([F,Cl,Br,I])cccc1
+acidHalide C(=O)[Cl,Br,I,F]
+acyclic-C=C-O C=[C!r]O
+acylCyanide N#CC(=O)
+acylHydrazine C(=O)N[NH2]
+aldehyde [CH1](=O)
+Aliphatic-long-chain [R0;D2][R0;D2][R0;D2][R0;D2]
+alkyl-halide [CX4][Cl,Br,I]
+amidotetrazole c1nnnn1C=O
+aniline c1cc([NH2])ccc1
+azepane [CH2R2]1N[CH2R2][CH2R2][CH2R2][CH2R2][CH2R2]1
+Azido-group N=[N+]=[N-]
+Azo-group N#N
+azocane [CH2R2]1N[CH2R2][CH2R2][CH2R2][CH2R2][CH2R2][CH2R2]1
+benzidine [cR2]1[cR2][cR2]([Nv3X3,Nv4X4])[cR2][cR2][cR2]1[cR2]2[cR2][cR2][cR2]([Nv3X3,Nv4X4])[cR2][cR2]2
+betaketo/anhydride [C,c](=O)[CX4,CR0X3,O][C,c](=O)
+biotin-analogue C12C(NC(N1)=O)CSC2
+Carbo-cation/anion [C+,c+,C-,c-]
+catechol c1c([OH])c([OH,NH2,NH])ccc1
+charged-oxygen/sulfur-atoms [O+,o+,S+,s+]
+chinone C1(=[O,N])C=CC(=[O,N])C=C1
+chinone C1(=[O,N])C(=[O,N])C=CC=C1
+conjugated-nitrile-group C=[C!r]C#N
+crown-ether [OR2,NR2]@[CR2]@[CR2]@[OR2,NR2]@[CR2]@[CR2]@[OR2,NR2]
+cumarine c1ccc2c(c1)ccc(=O)o2
+cyanamide N[CH2]C#N
+cyanate/aminonitrile/thiocyanate [N,O,S]C#N
+cyanohydrins N#CC[OH]
+cycloheptane [CR2]1[CR2][CR2][CR2][CR2][CR2][CR2]1
+cycloheptane [CR2]1[CR2][CR2]cc[CR2][CR2]1
+cyclooctane [CR2]1[CR2][CR2][CR2][CR2][CR2][CR2][CR2]1
+cyclooctane [CR2]1[CR2][CR2]cc[CR2][CR2][CR2]1
+diaminobenzene [cR2]1[cR2]c([N+0X3R0,nX3R0])c([N+0X3R0,nX3R0])[cR2][cR2]1
+diaminobenzene [cR2]1[cR2]c([N+0X3R0,nX3R0])[cR2]c([N+0X3R0,nX3R0])[cR2]1
+diaminobenzene [cR2]1[cR2]c([N+0X3R0,nX3R0])[cR2][cR2]c1([N+0X3R0,nX3R0])
+diazo-group [N!R]=[N!R]
+diketo-group [C,c](=O)[C,c](=O)
+disulphide SS
+enamine [CX2R0][NX3R0]
+ester-of-HOBT C(=O)Onnn
+four-member-lactones C1(=O)OCC1
+halogenated-ring c1cc([Cl,Br,I,F])cc([Cl,Br,I,F])c1[Cl,Br,I,F]
+halogenated-ring c1ccc([Cl,Br,I,F])c([Cl,Br,I,F])c1[Cl,Br,I,F]
+heavy-metal [Hg,Fe,As,Sb,Zn,Se,se,Te,B,Si]
+het-C-het-not-in-ring [NX3R0,NX4R0,OR0,SX2R0][CX4][NX3R0,NX4R0,OR0,SX2R0]
+hydantoin C1NC(=O)NC(=O)1
+hydrazine N[NH2]
+hydroquinone [OH]c1ccc([OH,NH2,NH])cc1
+hydroxamic-acid C(=O)N[OH]
+imine C=[N!R]
+imine N=[CR0][N,n,O,S]
+iodine I
+isocyanate N=C=O
+isolate-alkene [$([CH2]),$([CH][CX4]),$(C([CX4])[CX4])]=[$([CH2]),$([CH][CX4]),$(C([CX4])[CX4])]
+ketene C=C=O
+methylidene-1,3-dithiole S1C=CSC1=S
+Michael-acceptor C=!@CC=[O,S]
+Michael-acceptor [$([CH]),$(CC)]#CC(=O)[C,c]
+Michael-acceptor [$([CH]),$(CC)]#CS(=O)(=O)[C,c]
+Michael-acceptor C=C(C=O)C=O
+Michael-acceptor [$([CH]),$(CC)]#CC(=O)O[C,c]
+N-oxide [NX2,nX3][OX1]
+N-acyl-2-amino-5-mercapto-1,3,4-thiadiazole s1c(S)nnc1NC=O
+N-C-halo NC[F,Cl,Br,I]
+N-halo [NX3,NX4][F,Cl,Br,I]
+N-hydroxyl-pyridine n[OH]
+nitro-group [N+](=O)[O-]
+N-nitroso [#7]-N=O
+oxime [C,c]=N[OH]
+oxime [C,c]=NOC=O
+Oxygen-nitrogen-single-bond [OR0,NR0][OR0,NR0]
+perfluorinated-chain [CX4](F)(F)[CX4](F)F
+peroxide OO
+phenol-ester c1ccccc1OC(=O)[#6]
+phenyl-carbonate c1ccccc1OC(=O)O
+phosphor-P-phthalimide [cR,CR]~C(=O)NC(=O)~[cR,CR]
+Polycyclic-aromatic-hydrocarbon a1aa2a3a(a1)A=AA=A3=AA=A2
+Polycyclic-aromatic-hydrocarbon a21aa3a(aa1aaaa2)aaaa3
+Polycyclic-aromatic-hydrocarbon a31a(a2a(aa1)aaaa2)aaaa3
+polyene [CR0]=[CR0][CR0]=[CR0]
+quaternary-nitrogen [s,S,c,C,n,N,o,O]~[nX3+,NX3+](~[s,S,c,C,n,N])~[s,S,c,C,n,N]
+quaternary-nitrogen [s,S,c,C,n,N,o,O]~[n+,N+](~[s,S,c,C,n,N,o,O])(~[s,S,c,C,n,N,o,O])~[s,S,c,C,n,N,o,O]
+quaternary-nitrogen [*]=[N+]=[*]
+saponine-derivative O1CCCCC1OC2CCC3CCCCC3C2
+silicon-halogen [Si][F,Cl,Br,I]
+stilbene c1ccccc1C=Cc2ccccc2
+sulfinic-acid [SX3](=O)[O-,OH]
+Sulfonic-acid [C,c]S(=O)(=O)O[C,c]
+Sulfonic-acid S(=O)(=O)[O-,OH]
+sulfonyl-cyanide S(=O)(=O)C#N
+sulfur-oxygen-single-bond [SX2]O
+sulphate OS(=O)(=O)[O-]
+sulphur-nitrogen-single-bond [SX2H0][N]
+Thiobenzothiazole c12ccccc1(SC(S)=N2)
+thiobenzothiazole c12ccccc1(SC(=S)N2)
+Thiocarbonyl-group [C,c]=S
+thioester SC=O
+thiol [S-]
+thiol [SH]
+Three-membered-heterocycle *1[O,S,N]*1
+triflate OS(=O)(=O)C(F)(F)F
+triphenyl-methylsilyl [SiR0,CR0](c1ccccc1)(c2ccccc2)(c3ccccc3)
+triple-bond C#C