Translating data to predictive models
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Biological, chemical and physical properties of molecules are encoded in their molecular structure. The challenge lies in discovering the relationships between the molecular graphs and the measured activity. Where data is measured, collected and curated for a series of compounds there is an opportunity to find the hidden relationships. Chemical structures come in various shapes and sizes, depending on the scientists or even algorithms that create them. Though variability may sometimes seem subtle to a trained chemist’s eyes, these can introduce inconsistencies that impair chemical search algorithms or model building. Structure normalization is a key component of any cheminformatics workflow with an often underestimated significance. Finding relationships between chemical structures and their measured properties primarily relies on the representation of the chemical matter. Variability of the calculated features and descriptors for these representations can influence data analysis and accuracy of the predictions. During the first part of the presentation we will present the effect of chemical normalization on investigating correlations and building predictive models. The second part of the talk will incorporate the results of model building on 163 ChEMBL targets extracted from the bioactivity benchmark set1. Results with different descriptor generation methods including ECFP fingerprints, MACCS key, structural properties, geometry properties and phy-chem properties will be discussed in detail. This part focuses on summarizing the results of more than 3000 Random Forest models. Finally model development for ADMET targets will be highlighted including hERG cardiotoxicity prediction, permeability and blood brain barrier penetration. We will describe how these models can be built, analyzed, optimized and deployed using our new machine learning platform.
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Translating data to predictive models
- 1. Translating data to predictive models Akos Tarcsay
- 4. From data to prediction Data ingestion Preprocessing Modelling Features Models Review Prediction Model repository
- 5. Chemaxon Descriptor generation Chemaxon Standardizer Persistence and search System overview DB layer PostgreSQL Statistical evaluation ML library (SMILE) Conformal prediction wrapper Service layer Programmatic access REST interface “Comp Chem” Trainer GUI “Med Chem” Prediction GUI
- 6. How to reduce noise? Preprocessing
- 7. Effect of standardization - Simple descriptors (Mw, fsp3, HBDA, etc. ) Imipramine pamoate Furan-2-ol - Phys-chem (logD, pKa) - Molecular graph, Fingerprints Salts, solvates Tautomerism “Overall and despite our efforts to use open software wherever possible, we find that ChemAxon Tautomers node outperforms the other approaches we tested.” https://jcheminf.biomedcentral.com/articles/10.1186/s13321-022-00606-7
- 8. Small molecule retention time (SMRT) dataset: Tautomerization https:/ /www.nature.com/articles/s41467-019-13680-7
- 9. SMRT Tautomer example, edge case Training set: single tautomer random 7k cases Test set: tautomerization affected 252 cases Run with and without tautomerization
- 11. SMRT results https:/ /www.nature.com/articles/s41467-019-13680-7 ChemAxon Trainer Engine Original publication 15k test compounds, R2 =0.9
- 13. Activity dataset: the ‘ChEMBL bioactivity benchmark set’ Data source: Journal of Cheminformatics, 9, 45 (2017) by Eelke B. Lenselink, Niels ten Dijke, Brandon Bongers, George Papadatos, Herman W. T. van Vlijmen, Wojtek Kowalczyk, Adriaan P. IJzerman, Gerard J. P. van Westen - ChEMBL database (version 20) - Activities were selected that met the following criteria: - at least 30 compounds tested per protein and from at least 2 separate publications - assay confidence score of 9 - ‘single protein’ target type - assigned pCHEMBL value - no flags on potential duplicate or data validity comment - originating from scientific literature - data points with activity comments ‘not active’, ‘inactive’, ‘inconclusive’, and ‘undetermined’ were removed - MED value was chosen https:/ /jcheminf.biomedcentral.com/articles/10.1186/s13321-017-0232-0
- 14. Application Study on ChEMBL - Data points in range: 500-4703 (med:776) - 161 ChEMBL targets, pAct - Sorted by Document Year, last 30 points reserved as External set: Ext Last 30 Ext
- 15. Application Study on ChEMBL - Data points in range: 500-4703 (med:776) - 161 ChEMBL targets, pAct - Sorted by Document Year, last 30 points reserved as External set: Ext - 10-90% test-training set split: Test - ~160k total training size - ~18k total test size - 20 different descriptor configurations - Random Forest Rnd 90% Train Last 30 Ext Rnd 10% Test ...
- 17. Benchmark on 161 ChEMBL targets, best single configuration 161 ChEMBL Targets
- 18. Analysis of the best models per target Pearson R2 Ext Test Ext Test Avg 0.672 0.824 0.306 0.679 Median 0.722 0.833 0.385 0.697
- 20. Is it a hard task? Original results random split https:/ /jcheminf.biomedcentral.com/articles/10.1186/s13321-017-0232-0 “The best method overall is the DNN_MC with an MCC of 0.57 (±0.07)”
- 21. Is it a hard task? Original results temporal split https:/ /jcheminf.biomedcentral.com/articles/10.1186/s13321-017-0232-0
- 22. Classification case: class balance
- 23. Random Forest results RF MCC Ext Test Avg 0.310 0.541 Median 0.282 0.589
- 24. Is it a hard task? Base model: MPNN https:/ /keras.io/examples/graph/mpnn-molecular-graphs/ atom_featurizer = AtomFeaturizer( allowable_sets={ "symbol": {"B", "Br", "C", "Ca", "Cl", "F", "H", "I", "N", "Na", "O", "P", "S"}, "n_valence": {0, 1, 2, 3, 4, 5, 6}, "n_hydrogens": {0, 1, 2, 3, 4}, "hybridization": {"s", "sp", "sp2", "sp3"}, } ) bond_featurizer = BondFeaturizer( allowable_sets={ "bond_type": {"single", "double", "triple", "aromatic"}, "conjugated": {True, False}, } )
- 25. MCC reverse cumulative histogram Random split Test case RF MPNN MCC Ext Test Ext Test Avg 0.310 0.541 0.207 0.471 Median 0.282 0.589 0.178 0.493
- 26. Binned MCC evaluation random selected Test case MCC<0.45: Low 0.45<MCC<0.65: Medium 0.65<MCC: High
- 27. Binned MCC evaluation random selected Test case MCC<0.45: Low 0.45<MCC<0.65: Medium 0.65<MCC: High
- 28. MCC reverse cumulative histogram Temporal split Ext case RF MPNN MCC Ext Test Ext Test Avg 0.310 0.541 0.207 0.471 Median 0.282 0.589 0.178 0.493
- 29. Binned MCC evaluation temporal split Ext case MCC<0.45: Low 0.45<MCC<0.65: Medium 0.65<MCC: High
- 30. Binned MCC evaluation temporal split Ext case MCC<0.45: Low 0.45<MCC<0.65: Medium 0.65<MCC: High
- 32. Conformal prediction Proper Training Set Model Error model Calibration set Error Prediction Training Set P(80%) calibration factor (ɑ) https:/ /www.jmlr.org/papers/volume9/shafer08a/shafer08a.pdf https:/ /pubs.acs.org/doi/10.1021/ci5001168
- 33. Conformal prediction Proper Training Set Model Error model Calibration set Error Prediction Training Set P(80%) calibration factor (ɑ) Test: 14233 / 17661 80.6% within the error bound Ext: 3344 / 4890 68.4% within the error bound
- 35. AVG prediction time per set Descriptor: ECFP6_1024_MACCS_PHYSCHEM Intel(R) Xeon(R) CPU E3-1270 v3 @ 3.50GHz ~50 ms/ cpd 72k cpd /h
- 36. Drill down to the lowest performance set
- 37. Drill down to the lowest performance set TC_key: CHEMBL247 - CHEMBL2373969 BIOACT_PCHEMBL_VALUE: 7.54 TGT_CHEMBL_ID: CHEMBL247 TGT_ORGANISM: Human immunodeficiency virus 1
- 38. Feature engineering is the process of using domain knowledge to extract features from raw data.
- 39. Combined descriptor set ∑ 20 *161 =3220 descriptor sets
- 40. RF Importance (ECFP4_CHEMTERM:All) Sum of node impurity decreases for each individual variable over trees. Importance based rank is evaluated
- 41. RF Importance (ECFP4_CHEMTERM:All) 50% related to protonation or partitioning
- 44. Protonation de-tour: Fentanyl F-derivative: FF3 https:/ /www.nature.com/articles/s41598-019-55886-1 No difference at pH 6.5 10x MOR IC50 difference at pH 7.4
- 45. Statistical Assessment of the Modeling of Proteins and Ligands, SAMPL6 challenge logP https:/ /chemaxon.com/news/cxn-logp-prediction-sampl-6
- 48. Classification use case: Blood-Brain Barrier Penetration
- 49. Blood brain barrier penetration model MoleculeNet, 10.1039/c7sc02664a
- 50. Model analysis
- 52. Classification use case: PAMPA Permeability
- 53. Data preparation 1) Source: PubChem BioAssay AID: 1508612 a) NCATS Parallel Artificial Membrane Permeability Assay (PAMPA) Profiling b) Observed PAMPA at pH 7.4 (x 10-6 cm/sec) 2) Standardize (strip salts, tautomerize) 3) Mw 0-800 -> 2029 cases 4) Permeability 100 cutoff using “Phenotype” field 0:Low, Medium (646 cases) 1:High (1383 cases)
- 54. Clustering MACCS similarity matrix tSNE projection
- 55. Is it a hard task? Base model: MPNN Epoch 40/40 Train: AUC: 0.7897 MCC: 0.3921 Validation: AUC: 0.5879 MCC: 0.0740 https:/ /keras.io/examples/graph/mpnn-molecular-graphs/ atom_featurizer = AtomFeaturizer( allowable_sets={ "symbol": {"B", "Br", "C", "Ca", "Cl", "F", "H", "I", "N", "Na", "O", "P", "S"}, "n_valence": {0, 1, 2, 3, 4, 5, 6}, "n_hydrogens": {0, 1, 2, 3, 4}, "hybridization": {"s", "sp", "sp2", "sp3"}, } ) bond_featurizer = BondFeaturizer( allowable_sets={ "bond_type": {"single", "double", "triple", "aromatic"}, "conjugated": {True, False}, } )
- 56. MPNN: Epoch 40/40 Train: AUC: 0.7897 MCC: 0.3921 Validation: AUC: 0.5879 MCC: 0.0740
- 58. Data source: Scientific Reports vol 9, 12220 (2019) Keiji Ogura, Tomohiro Sato, Hitomi Yuki, Teruki Honma - 9 890 hERG inhibitors (IC50 ≤ 10 μM or ≥50% inhibition at 10 μM) - 281 329 inactive compounds (IC50 > 10 μM or <50% inhibition at 10 μM) according to their standardized chemical structures - 204k training data points - 87k test data points - Descriptor set: ECFP6_2048_MACCS_PHYSCHEM Classification model https:/ /www.nature.com/articles/s41598-019-47536-3
- 60. CONVERTING DATA TO PROJECT TEAM INSIGHTS
- 62. Discovery teams Design Landscape Design Hub Series H1 H2 H3 H4 Discovery hub connecting chemical series, data, predictions and chemical project management
- 63. Discovery teams Analysis Design Hub Series H1 H2 H3 H4 Biological measurements
- 64. Discovery teams Biological data focus Design Hub Series Trainer GUI Training / Analysis Comp. Chem Trainer Engine H1 H2 H3 H4 Trainer Engine
- 65. Discovery teams Train&Deploy Production Models Design Hub Services Series Trainer GUI Training / Analysis Comp. Chem Trainer Engine H1 H2 H3 H4 Trainer Engine { } REST … API { } REST … API
- 66. Discovery teams Fill the gap Production Models Design Hub Services Series Trainer GUI Training / Analysis Comp. Chem Trainer Engine H1 H2 H3 H4 Trainer Engine { } REST … API { } REST … API
- 67. Discovery teams Multi parameter optimization Production Models Design Hub Services Series Trainer GUI Training / Analysis Comp. Chem Trainer Engine H1 H2 H3 H4 Trainer Engine
- 68. Local and global models
- 69. Local and global models
- 70. Translate data to reliable models Centralize model management Connect project team members and resources Track and manage discovery Design Hub Lower the barrier to adopt AI models in design Trainer Engine
- 71. Take away - Chemical standardization to reduce noise - Role of protonation and partitioning descriptors - Successful model building on large and diverse set of targets - ML inference, delivery to medicinal chemists
- 73. Thank you