Fragmenting Molecules
This notebook aims to show how a drug-like molecule can be fragmented using this framework, and how those fragments can be easily visualised using its built-in helper utilities.
To begin with we load in the molecule to be fragmented. Here we load Cobimetinib directly using its SMILES representation using the Open Force Field toolkit:
[1]:
from openff.toolkit.topology import Molecule
parent_molecule = Molecule.from_smiles(
"OC1(CN(C1)C(=O)C1=C(NC2=C(F)C=C(I)C=C2)C(F)=C(F)C=C1)[C@@H]1CCCCN1"
)
Next we create the fragmentation engine which will perform the actual fragmentation. Here we will use the recommended WBOFragmenter with default options:
[2]:
from openff.fragmenter.fragment import WBOFragmenter
frag_engine = WBOFragmenter()
# Export the engine's settings directly to JSON
frag_engine.json()
[2]:
'{"functional_groups": {"hydrazine": "[NX3:1][NX3:2]", "hydrazone": "[NX3:1][NX2:2]", "nitric_oxide": "[N:1]-[O:2]", "amide": "[#7:1][#6:2](=[#8:3])", "amide_n": "[#7:1][#6:2](-[O-:3])", "amide_2": "[NX3:1][CX3:2](=[OX1:3])[NX3:4]", "aldehyde": "[CX3H1:1](=[O:2])[#6:3]", "sulfoxide_1": "[#16X3:1]=[OX1:2]", "sulfoxide_2": "[#16X3+:1][OX1-:2]", "sulfonyl": "[#16X4:1](=[OX1:2])=[OX1:3]", "sulfinic_acid": "[#16X3:1](=[OX1:2])[OX2H,OX1H0-:3]", "sulfinamide": "[#16X4:1](=[OX1:2])(=[OX1:3])([NX3R0:4])", "sulfonic_acid": "[#16X4:1](=[OX1:2])(=[OX1:3])[OX2H,OX1H0-:4]", "phosphine_oxide": "[PX4:1](=[OX1:2])([#6:3])([#6:4])([#6:5])", "phosphonate": "[P:1](=[OX1:2])([OX2H,OX1-:3])([OX2H,OX1-:4])", "phosphate": "[PX4:1](=[OX1:2])([#8:3])([#8:4])([#8:5])", "carboxylic_acid": "[CX3:1](=[O:2])[OX1H0-,OX2H1:3]", "nitro_1": "[NX3+:1](=[O:2])[O-:3]", "nitro_2": "[NX3:1](=[O:2])=[O:3]", "ester": "[CX3:1](=[O:2])[OX2H0:3]", "tri_halide": "[#6:1]([F,Cl,I,Br:2])([F,Cl,I,Br:3])([F,Cl,I,Br:4])"}, "scheme": "WBO", "wbo_options": {"method": "am1-wiberg-elf10", "max_conformers": 800, "rms_threshold": 1.0}, "threshold": 0.03, "heuristic": "path_length", "keep_non_rotor_ring_substituents": false}'
Use the engine to fragment the molecule:
[3]:
result = frag_engine.fragment(parent_molecule)
# Export the result directly to JSON
result.json()
[3]:
'{"parent_smiles": "[H:31][c:1]1[c:3]([c:9]([c:11]([c:8]([c:6]1[C:13](=[O:25])[N:23]2[C:18]([C:21]([C:19]2([H:46])[H:47])([C@@:20]3([C:16]([C:14]([C:15]([C:17]([N:22]3[H:49])([H:42])[H:43])([H:38])[H:39])([H:36])[H:37])([H:40])[H:41])[H:48])[O:26][H:51])([H:44])[H:45])[N:24]([H:50])[c:7]4[c:2]([c:4]([c:12]([c:5]([c:10]4[F:28])[H:35])[I:30])[H:34])[H:32])[F:29])[F:27])[H:33]", "fragments": [{"smiles": "[H:34][c:4]1[c:12]([c:5]([c:10]([c:7]([c:2]1[H:32])[N:24]([H:50])[c:8]2[c:6]([c:1]([c:3]([c:9]([c:11]2[F:29])[F:27])[H:33])[H:31])[C:13](=[O:25])[N:23]3[C:18]([C:21]([C:19]3([H:46])[H:47])([H])[H])([H:44])[H:45])[F:28])[H:35])[H]", "bond_indices": [8, 24]}, {"smiles": "[H:48][C@:20]1([C:16]([C:14]([C:15]([C:17]([N:22]1[H:49])([H:42])[H:43])([H:38])[H:39])([H:36])[H:37])([H:40])[H:41])[C:21]2([C:18]([N:23]([C:19]2([H:46])[H:47])[C:13](=[O:25])[C:6]([H])([H])[H])([H:44])[H:45])[O:26][H:51]", "bond_indices": [20, 21]}, {"smiles": "[H:34][c:4]1[c:12]([c:5]([c:10]([c:7]([c:2]1[H:32])[N:24]([H:50])[c:8]2[c:6]([c:1]([c:3]([c:9]([c:11]2[F:29])[H])[H:33])[H:31])[C:13](=[O:25])[N:23]3[C:18]([C:21]([C:19]3([H:46])[H:47])([H])[H])([H:44])[H:45])[F:28])[H:35])[H]", "bond_indices": [7, 24]}, {"smiles": "[H:33][c:3]1[c:9]([c:11]([c:8]([c:6]([c:1]1[H:31])[C:13](=[O:25])[N:23]2[C:18]([C:21]([C:19]2([H:46])[H:47])([H])[H])([H:44])[H:45])[N:24]([H:50])[C:7]([H])([H])[H])[H])[H]", "bond_indices": [13, 23]}, {"smiles": "[H:33][c:3]1[c:1]([c:6]([c:8]([c:11]([c:9]1[H])[F:29])[N:24]([H:50])[C:7]([H])([H])[H])[C:13](=[O:25])[N:23]2[C:18]([C:21]([C:19]2([H:46])[H:47])([H])[H])([H:44])[H:45])[H:31]", "bond_indices": [6, 13]}], "provenance": {"creator": "openff.fragmenter", "version": "0.0.7+17.g8b49361.dirty", "options": {"functional_groups": {"hydrazine": "[NX3:1][NX3:2]", "hydrazone": "[NX3:1][NX2:2]", "nitric_oxide": "[N:1]-[O:2]", "amide": "[#7:1][#6:2](=[#8:3])", "amide_n": "[#7:1][#6:2](-[O-:3])", "amide_2": "[NX3:1][CX3:2](=[OX1:3])[NX3:4]", "aldehyde": "[CX3H1:1](=[O:2])[#6:3]", "sulfoxide_1": "[#16X3:1]=[OX1:2]", "sulfoxide_2": "[#16X3+:1][OX1-:2]", "sulfonyl": "[#16X4:1](=[OX1:2])=[OX1:3]", "sulfinic_acid": "[#16X3:1](=[OX1:2])[OX2H,OX1H0-:3]", "sulfinamide": "[#16X4:1](=[OX1:2])(=[OX1:3])([NX3R0:4])", "sulfonic_acid": "[#16X4:1](=[OX1:2])(=[OX1:3])[OX2H,OX1H0-:4]", "phosphine_oxide": "[PX4:1](=[OX1:2])([#6:3])([#6:4])([#6:5])", "phosphonate": "[P:1](=[OX1:2])([OX2H,OX1-:3])([OX2H,OX1-:4])", "phosphate": "[PX4:1](=[OX1:2])([#8:3])([#8:4])([#8:5])", "carboxylic_acid": "[CX3:1](=[O:2])[OX1H0-,OX2H1:3]", "nitro_1": "[NX3+:1](=[O:2])[O-:3]", "nitro_2": "[NX3:1](=[O:2])=[O:3]", "ester": "[CX3:1](=[O:2])[OX2H0:3]", "tri_halide": "[#6:1]([F,Cl,I,Br:2])([F,Cl,I,Br:3])([F,Cl,I,Br:4])"}, "scheme": "WBO", "wbo_options": {"method": "am1-wiberg-elf10", "max_conformers": 800, "rms_threshold": 1.0}, "threshold": 0.03, "heuristic": "path_length", "keep_non_rotor_ring_substituents": false}, "toolkits": [["OpenEyeToolkitWrapper", "2020.2.2"], ["RDKitToolkitWrapper", "2021.03.1"], ["AmberToolsToolkitWrapper", "20.0"], ["BuiltInToolkitWrapper", null]]}}'
Any generated fragments will be returned in a FragmentationResult object. We can loop over each of the generated fragments and print both the SMILES representation of the fragment as well as the map indices of the bond that the fragment was built around:
[4]:
for fragment in result.fragments:
print(f"{fragment.bond_indices}: {fragment.smiles}")
(8, 24): [H:34][c:4]1[c:12]([c:5]([c:10]([c:7]([c:2]1[H:32])[N:24]([H:50])[c:8]2[c:6]([c:1]([c:3]([c:9]([c:11]2[F:29])[F:27])[H:33])[H:31])[C:13](=[O:25])[N:23]3[C:18]([C:21]([C:19]3([H:46])[H:47])([H])[H])([H:44])[H:45])[F:28])[H:35])[H]
(20, 21): [H:48][C@:20]1([C:16]([C:14]([C:15]([C:17]([N:22]1[H:49])([H:42])[H:43])([H:38])[H:39])([H:36])[H:37])([H:40])[H:41])[C:21]2([C:18]([N:23]([C:19]2([H:46])[H:47])[C:13](=[O:25])[C:6]([H])([H])[H])([H:44])[H:45])[O:26][H:51]
(7, 24): [H:34][c:4]1[c:12]([c:5]([c:10]([c:7]([c:2]1[H:32])[N:24]([H:50])[c:8]2[c:6]([c:1]([c:3]([c:9]([c:11]2[F:29])[H])[H:33])[H:31])[C:13](=[O:25])[N:23]3[C:18]([C:21]([C:19]3([H:46])[H:47])([H])[H])([H:44])[H:45])[F:28])[H:35])[H]
(13, 23): [H:33][c:3]1[c:9]([c:11]([c:8]([c:6]([c:1]1[H:31])[C:13](=[O:25])[N:23]2[C:18]([C:21]([C:19]2([H:46])[H:47])([H])[H])([H:44])[H:45])[N:24]([H:50])[C:7]([H])([H])[H])[H])[H]
(6, 13): [H:33][c:3]1[c:1]([c:6]([c:8]([c:11]([c:9]1[H])[F:29])[N:24]([H:50])[C:7]([H])([H])[H])[C:13](=[O:25])[N:23]2[C:18]([C:21]([C:19]2([H:46])[H:47])([H])[H])([H:44])[H:45])[H:31]
Finally, we can visualize the produced fragments:
[5]:
from openff.fragmenter.depiction import depict_fragmentation_result
depict_fragmentation_result(result=result, output_file="example_fragments.html")
from IPython.core.display import HTML
with open("example_fragments.html") as file:
display(HTML(file.read()))
