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Update stereoisomerism_QSAR.ipynb
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Fixed some typos! Should be all okay now.
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"cell_type": "markdown",
"metadata": {},
"source": [
"The molecule is `chiral` with one stereocenter at `atom 10`, meaning that that atom is bound to 4 different groups: a metheyl, a carboxylic acid, a subtituted aromtic ring, and a hydrogen atom (the latter usually not shown in 2D representations).\n",
"The molecule is `chiral` with one stereocenter at `atom 10`, meaning that that atom is bound to 4 different groups: a methyl, a carboxylic acid, a substituted aromatic ring, and a hydrogen atom (the latter usually not shown in 2D representations).\n",
"\n",
"`Chirality` is the property of compounds that posses the same molecular formula and atom connectivity, but exist in different 3D configurations that are a `non-superimposable mirror image of each other`, similarly to your left and right hand! The different steroisomers of chiral compounds interact differently with beams of polarized light in a phenomenon called `optical isomerism`.\n",
"`Chirality` is the property of compounds that posses the same molecular formula and atom connectivity, but exist in different 3D configurations that are a `non-superimposable mirror image of each other`, similarly to your left and right hand! The different stereoisomers of chiral compounds interact differently with beams of polarized light in a phenomenon called `optical isomerism`.\n",
"\n",
"Let's have a look at all the potential stereoisomers for Ibuprofen."
]
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"source": [
"If we 'flat' the aromatic and carboxylic acid groups in the plane of your screen, the methyl group attached to the chiral carbon atom can be pointing `up` towards you or `down` away from you (remember that C atoms have a tetrahedral disposition of the four groups bound to it; hydrogen atoms are usually omitted in 2D representations).\n",
"\n",
"The molecule posseses a `single chiral center` that originates `two possible stereoisomers`. These two stereoisomers are the non-superimposeable mirror image of each other thus they are commonly referred as `enantiomers`.\n",
"The molecule posseses a `single chiral center` that originates `two possible stereoisomers`. These two stereoisomers are the non-superimposable mirror image of each other thus they are commonly referred as `enantiomers`.\n",
"\n",
"Let's look at the same enantiomers in 3D:"
]
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"metadata": {},
"source": [
"Molecules are often converted to `rdkit.mol` objects before being transformed other advanced features vectors. \n",
"Different stereiosmers are detected as differernt `rdkit.mol` object (as it should be!):"
"Different stereiosmers are detected as different `rdkit.mol` object (as it should be!):"
]
},
{
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"source": [
"We have briefly explored stereisomers generated by the presence of a chiral atom, but that is not the only case in which a compound can exist as different stereisomers.\n",
"\n",
"Another common case of stereisomerism is the `E/Z isomerism`. This form of stereisomerism arises from the different arrangment of groups bound via a `double bond`. The most common cases are compounds containing a `C=C` double bond, but also `C=N` and `N=N` can be commonly found in nature.\n",
"Another common case of stereisomerism is the `E/Z isomerism`. This form of stereisomerism arises from the different arrangement of groups bound via a `double bond`. The most common cases are compounds containing a `C=C` double bond, but also `C=N` and `N=N` can be commonly found in nature.\n",
"The `E/Z` nomenclature derives from German for `E`ntegen (opposite) and `Z`usammen (together). In the past another nomenclature for double bond stereochemistry was utilized where E and Z were replaced by 'trans' and 'cis', respectively, but this type of notation is now deprecated and utilized for other scopes.\n",
"\n",
"Due to the nature of double bonds, the four substituents (two for each carbon atom) are `all placed in the same plane` but they can point in different directions such as in the case of 1-bromo-2-chrloropropene:"
"Due to the nature of double bonds, the four substituents (two for each carbon atom) are `all placed in the same plane` but they can point in different directions such as in the case of 1-bromo-2-chloropropene:"
]
},
{
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"cell_type": "markdown",
"metadata": {},
"source": [
"As before, we can see that the two possible stereisomers have the same type of atoms and the same connectivity, but quite evidently `the two halogen atoms (bromo and chloro) can either be placed on the same or the opposide 'side' of the C=C double bond`'\n",
"As before, we can see that the two possible stereisomers have the same type of atoms and the same connectivity, but quite evidently `the two halogen atoms (bromo and chloro) can either be placed on the same or the opposite 'side' of the C=C double bond`'\n",
"\n",
"Similarily to chiral centers, SMILES strings have a special symbol to identify E/Z isomers: `\\` or `/`:"
"Similarly to chiral centers, SMILES strings have a special symbol to identify E/Z isomers: `\\` or `/`:"
]
},
{
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"cell_type": "markdown",
"metadata": {},
"source": [
"We have seen moelcules that contain a single chiral center or a double bond and how we define their correspoding stereisomers.\n",
"Nature is very often a bit more creative, and it is very common to ecnoutenr compounds that contains `multiple chiral atoms and/or one or more double bonds`!\n",
"We have seen molecules that contain a single chiral center or a double bond and how we define their corresponding stereisomers.\n",
"Nature is very often a bit more creative, and it is very common to encounter compounds that contains `multiple chiral atoms and/or one or more double bonds`!\n",
"\n",
"Please, refer to the diagram at the beginning of this tutorial for a complete overview of all the possibilities but here a couple of examples of compounds containing multiple types of stereochemical information:"
]
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"### Is stereochemistry always important in QSAR?\n",
"\n",
"Short answer: `YES!`\n",
"The 3D arragnemtn of groups in a molecule has a profound impact on how different stereisomers interact with biological targets. Remember that every single protein is nothing more that a very big molecule that contains a large amount of chiral centers, therefore `proteins and biological entities are stereisomers themselves`.\n",
"Different stereisomers (e.g., enantiomers, diastereisomers) will interact differently with their biological targets showing vastly different pharmacology, binding affinity, activty and potency, etc...\n",
"The 3D arrangement of groups in a molecule has a profound impact on how different stereisomers interact with biological targets. Remember that every single protein is nothing more that a very big molecule that contains a large amount of chiral centers, therefore `proteins and biological entities are stereisomers themselves`.\n",
"Different stereisomers (e.g., enantiomers, diastereisomers) will interact differently with their biological targets showing vastly different pharmacology, binding affinity, activity and potency, etc...\n",
"\n",
"**Examples**: \n",
"The binding site of the β2-adrenergic receptor has a specific 3D shape where (R)-albuterol fits into more precisely than the (S)-albuterol. (R)-albuterol provides more effective treatment with fewer side effects targeting β2-adrenergic receptors in comparison to (S)-albuterol.\n",
"Another example is Penicillamine, where the (S) enantiomer shows the desired antiarthritic activity, whereas the (R) enantiomer is extremely toxic!\n",
"\n",
"In the `rare cases` where stereochemistry is found not to affect the biological activity of a series of compounds, the stereochemical information may be uncessessary in handling these datasets (always check before removing or ignoring stereochemistry).\n",
"\n",
"Furthermore, stereochemistry may have also an impact on the `physical` (e.g., solubility, melting point) and `pysicochemical` (e.g., logP, TPSA) properties of a molecule, but not always:\n",
"Furthermore, stereochemistry may have also an impact on the `physical` (e.g., solubility, melting point) and `physiochemical` (e.g., logP, TPSA) properties of a molecule, but not always:\n",
" - `Enantiomers` always show the same physical and physicochemical properties;\n",
" - `Diastereisomers` often show different physical properties but they have the same physicochemical properties.\n",
"\n",
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"\n",
"Undefined or partially defined stereochmical information is unfortunately quite common, especially in the early stages of a drug developement program, and it usually challenges efforts in QSAR modeling.\n",
"\n",
"It is worth mentioning that, in early-stage drug dicsovery programs, where high-throughput screening (HTS) is utilized to identify hit compouds from very large libraries, the focus is more oritented towards broad activity trends rather than precise stereochemical interactions. As a result, at this stage, stereochemistry may be ignored by rotuinely testing racemic mixtures (mixtures containg equal amounts of the possible enantiomers), and mistures of diastereisomers.\n",
"Therefore, when utilizing models trained on such data lacking accurate stereochemical inforamtion, it is important to specify the limitations of these models, particularly regarding their applicability to other molecular databases.\n"
"It is worth mentioning that, in early-stage drug discovery programs, where high-throughput screening (HTS) is utilized to identify hit compouds from very large libraries, the focus is more oritented towards broad activity trends rather than precise stereochemical interactions. As a result, at this stage, stereochemistry may be ignored by routinely testing racemic mixtures (mixtures containg equal amounts of the possible enantiomers), and mistures of diastereisomers.\n",
"Therefore, when utilizing models trained on such data lacking accurate stereochemical information, it is important to specify the limitations of these models, particularly regarding their applicability to other molecular databases.\n"
]
},
{
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"name": "stdout",
"output_type": "stream",
"text": [
"This featurizer 'ecfp:4' can't differenciate the two enantiomers!\n"
"This featurizer 'ecfp:4' can't differentiate the two enantiomers!\n"
]
}
],
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"fp1 = transfomer_1(mol1_3d)\n",
"fp2 = transfomer_1(mol2_3d)\n",
"if np.array_equal(fp1, fp2):\n",
" print(f\"This featurizer '{transfomer_1.kind}' can't differenciate the two enantiomers!\")"
" print(f\"This featurizer '{transfomer_1.kind}' can't differentiate the two enantiomers!\")"
]
},
{
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"name": "stdout",
"output_type": "stream",
"text": [
"This featurizer 'ecfp:4' can't differenciate the two diastereoisomers!\n"
"This featurizer 'ecfp:4' can't differentiate the two diastereomers!\n"
]
}
],
"source": [
"fp3 = transfomer_1(mol3_3d)\n",
"fp4 = transfomer_1(mol4_3d)\n",
"if np.array_equal(fp3, fp4):\n",
" print(f\"This featurizer '{transfomer_1.kind}' can't differenciate the two diastereoisomers!\")"
" print(f\"This featurizer '{transfomer_1.kind}' can't differentiate the two diastereomers!\")"
]
},
{
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"name": "stdout",
"output_type": "stream",
"text": [
"This featurizer 'cats' can differenciate the enantiomers!\n"
"This featurizer 'cats' can differentiate the enantiomers!\n"
]
}
],
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"feat1 = transformer_2(mol1_3d)\n",
"feat2 = transformer_2(mol2_3d)\n",
"if not np.array_equal(feat1, feat2):\n",
" print(f\"This featurizer '{transformer_2.featurizer.factory}' can differenciate the enantiomers!\")"
" print(f\"This featurizer '{transformer_2.featurizer.factory}' can differentiate the enantiomers!\")"
]
},
{
Expand All @@ -1340,23 +1340,23 @@
"name": "stdout",
"output_type": "stream",
"text": [
"This featurizer 'cats' can differenciate the diastereoisomers!\n"
"This featurizer 'cats' can differentiate the diastereomers!\n"
]
}
],
"source": [
"feat3 = transformer_2(mol3_3d)\n",
"feat4 = transformer_2(mol4_3d)\n",
"if not np.array_equal(feat1, feat2):\n",
" print(f\"This featurizer '{transformer_2.featurizer.factory}' can differenciate the diastereoisomers!\")"
" print(f\"This featurizer '{transformer_2.featurizer.factory}' can differentiate the diastereomers!\")"
]
},
{
"attachments": {},
"cell_type": "markdown",
"metadata": {},
"source": [
"Please find more deatails about featurizer [pharm3D-cats](https://molfeat.datamol.io/featurizers/pharm3D-cats) and explore other available featurizers on [molfeat](https://molfeat.datamol.io/) page."
"Please find more details about featurizer [pharm3D-cats](https://molfeat.datamol.io/featurizers/pharm3D-cats) and explore other available featurizers on [molfeat](https://molfeat.datamol.io/) page."
]
},
{
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"cell_type": "markdown",
"metadata": {},
"source": [
"Careful data curation and autiding is essential to determine whether the observed bioactivity of a series of compounds is highly dependent on their stereochemistry or not.\n",
"`Auroris` simplifies and streamlines this process by providing the [StereoIsomerACDetection](https://github.com/polaris-hub/auroris/blob/3b8792a7d5c7fefbf08a2c0b087f99dc3fa69088/auroris/curation/actions/_ac_stereoisomer.py#L61) module and the corresponding [detect_streoisomer_activity_cliff](https://github.com/polaris-hub/auroris/blob/3b8792a7d5c7fefbf08a2c0b087f99dc3fa69088/auroris/curation/actions/_ac_stereoisomer.py#L15) function to easily assess this instances. \n",
"Careful data curation and auditing is essential to determine whether the observed bioactivity of a series of compounds is highly dependent on their stereochemistry or not.\n",
"`Auroris` simplifies and streamlines this process by providing the [StereoIsomerACDetection](https://github.com/polaris-hub/auroris/blob/3b8792a7d5c7fefbf08a2c0b087f99dc3fa69088/auroris/curation/actions/_ac_stereoisomer.py#L61) module and the corresponding [detect_stereoisomer_activity_cliff](https://github.com/polaris-hub/auroris/blob/3b8792a7d5c7fefbf08a2c0b087f99dc3fa69088/auroris/curation/actions/_ac_stereoisomer.py#L15) function to easily assess this instances. \n",
"\n",
"For guidance on how to combine different Auroris modules for small molecule dataset curation, please checkout this [tutorial](https://polaris-hub.github.io/auroris/stable/tutorials/getting_started.html)."
]
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