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What makes a compound and allosteric modulator?
- 1. What makes a compound an allosteric modulator? Physicochemical profiling of allosteric regulators of proteins Gerard JP van Westen Anna Gaulton John P Overington
- 2. Background… • Allosteric modulators enable small molecule modulation of targets that are infeasible to modulate orthosterically (e.g. Class B/C GPCRs). • Allosteric modulators often considered as back-up strategy. • Allosteric modulators to disturb PPIs?... • Allosteric modulators are interesting drugs..
- 3. Background… Göblyös, Anikó, and Ad P. IJzerman. "Allosteric modulation of adenosine receptors." Purinergic signalling 5.1 (2009): 51-61.
- 4. Background… • How do we define allostery?
- 5. Background… • Idea: what can we learn from ChEMBL with regard to allosteric modulators? ▫ We should be able to retrieve literature on allosteric modulation by searching for keywords in abstracts and titles of publications included in ChEMBL
- 6. Text mining approach • Searching for a number of terms (title and/or abstract): ▫ Uncompetitive ▫ un‐competitive ▫ Noncompetitive ▫ non‐competitive ▫ Allostery ▫ Alostery ▫ Activators ▫ Positive modulators ▫ Negative modulators ▫ Regulatory site ▫ NNRTI ▫ Positive modulator ▫ Negative modulator ▫ Secondary binding site ▫ Secondary pocket ▫ Nonsubstrate ▫ Allosteric ▫ Allosterism ▫ Alosteric ▫ Alosterism ▫ Indirectly inhibit ▫ Indirectly activate
- 7. Retrieved records +/- 6,000 documents in the ‘Journal Articles’ table ± 900 documents were in ChEMBL 17,197 bioactivity points (primary assay) 414 targets (primary assay) 16,762 unique compounds 10 L1 Target classes Bioactivity TargetsChemistry 17 L2 Target classes
- 8. After initial round of curation +/- 6,000 documents in the ‘Journal Articles’ table 991 documents were from ChEMBL 18,273 bioactivity points (primary assay) 417 targets (primary assay) 17,829 unique compounds 10 L1 Target classes Bioactivity TargetsChemistry 17 L2 Target classes
- 9. After initial round of curation Bioactivity
- 11. Summarized..
- 12. Targets…
- 13. Targets • ChEMBL target class hierarchy all protein binding compounds Enzyme Membrane Receptor HIV Reverse Transcriptase 7TM1 7TM2 7TM3 Adenosine receptor Metabotropic glutamate receptor L0 L1 L2 L8Glucagon receptor
- 16. Targets Conclusions • Distribution of target classes differs between allosteric and non-allosteric sets ▫ Some targets are apparently much easier to hit via allosteric modulation than via non-allosteric modulation (class C GPCRs). • Allosteric modulation cannot be considered a cure-for- difficult targets
- 17. Chemistry…
- 18. Chemistry • Allosteric modulators have a slightly lower molecular weight on average
- 19. Chemistry • Allosteric modulators have a slightly higher AlogP on average
- 20. Chemistry • Hydrogen bonding (1)
- 21. Chemistry • Hydrogen bonding (2)
- 23. • So allosteric modulators: ▫ Smaller, more lipophilic / less hydrogen bonding potential Chemistry
- 24. Chemistry • Allosteric modulators tend to adhere slightly better to Lipinski’s rule of 5 ▫ no violations allowed : Allosteric: 75 % Non-Allosteric: 70 %
- 26. Chemistry Conclusions • Difficult to draw firm conclusions on ‘allosteric modulators’, properties target dependent ▫ Allosteric modulation and non-allosteric modulation of targets can be considered different targets • Still, some trends with regard to physicochemical properties can be spotted
- 27. Bioactivity…
- 28. Bioactivity • Allosteric modulators are very similar to non-allosteric modulators with respect to bioactivity • Their absolute affinity tends to be slightly lower on average ▫ The binding efficiency index is similar due to the lower molecular weight (log affinity/ MW (kDa)) ▫ The surface efficiency index tends to be higher due to the lower polar surface area (log affinity / PSA-2) • Allosteric modulators occupy similar ‘high affinity’ hotspots as do orthosteric modulators C. Abad-Zapatero. ”Ligand efficiency indexes for efficient drug discovery" Expert Opin. Drug. Dicov. 2 (2007): 469-489
- 29. Bioactivity Shown is the median value of all compounds. Error is given by the median average deviation of the median (MAD) C. Abad-Zapatero. ”Ligand efficiency indexes for efficient drug discovery" Expert Opin. Drug. Dicov. 2 (2007): 469-489
- 30. Bioactivity • What is the cause for the lowered absolute affinity? ▫ … properties of binding pockets themselves ▫ … metabolites can make allosteric modulators and these tend to be present at very high local concentrations ▫ … • In any case we observe that the absolute affinity is lower… ▫ hence assay read-outs should be adopted to properly reflect this or possible (unoptimized) compounds can be missed
- 32. Bioactivity (Case study) • Kinases form a slightly different story ▫ Allosteric modulators can also be ligand-mimetic, hence peptides can be allosteric modulators in this case (opposite from class B GPCRs) Allosterics (peptides) Allosterics (small molecules) ▫ Orthosteric ligands (usually atp-competitive) actually form a more converse class in this case • Please remember this for later on..
- 33. So if Allosteric =/= Non-allosteric… …then can we model this classification?
- 34. Allosteric =/= Orthosteric Red is the model, Blue is random
- 35. Allosteric Models * • What properties are important? (L0) ▫ Property importance varies with target class Target Level Class Allosteric Compounds Orthosteric Compounds ROC Sensitivity Specificity PPV NPV MCC 0 n/a 17,197 509,257 0.90 0.70 0.93 0.24 0.99 0.38 Allosteric property 1 Allosteric property 2 Allosteric property 3 Non-Allosteric Property 1 Non-Allosteric Property 2 Non-Allosteric Property 3 AlogP Aromatic Bonds Frac Molecular Solubility * Molecular Volume Molecular Surface Area Molecular SASA Note that molecular solubility is a log concentration value, hence larger values indicate compounds are less soluble Note that these models have been retrained and improved after manual curation (results pending)..
- 36. So, what about individual target classes…?
- 37. Allosteric Models • Models follow ChEMBL target class hierarchy all protein binding compounds Enzyme Membrane Receptor HIV Reverse Transcriptase 7TM1 7TM2 7TM3 Adenosine receptor Metabotropic glutamate receptor L0 L1 L2 L8Glucagon receptor
- 38. Allosteric Models • What properties are important? (L1): Target Level Class Allosteric Compounds Non-allosteric Compounds ROC (OOB) Sensitivity Specificity PPV NPV MCC 1 Enzyme 8,445 212,885 0.91 0.75 0.93 0.29 0.99 0.43 Allosteric property 1 Allosteric property 2 Allosteric property 3 Non-Allosteric Property 1 Non-Allosteric Property 2 Non-Allosteric Property 3 AlogP Average Bondlength Molecular Solubility * Rotatable Bonds Frac Polar Surface Area Hydrogen Frac Note that molecular solubility is a log concentration value, hence larger values indicate compounds are less soluble Note that these models have been retrained and improved after manual curation (results pending)..
- 39. Allosteric Models • Sometimes the story is different (L1): ▫ Non-competitive with respect to regulator proteins, competitive with regard to ions Target Level Class Allosteric Compounds Orthosteric Compounds ROC (OOB) Sensitivity Specificity PPV NPV MCC 1 Ion Channel 1,974 23,871 0.93 0.77 0.93 0.50 0.98 0.58 Allosteric property 1 Allosteric property 2 Allosteric property 3 Non-Allosteric Property 1 Non-Allosteric Property 2 Non-Allosteric Property 3 Average Bondlength Hydrogen Frac Rotatable Bonds Frac Aromatic Bonds Frac N Count Frac AlogP Note that molecular solubility is a log concentration value, hence larger values indicate compounds are less soluble Note that these models have been retrained and improved after manual curation (results pending)..
- 40. Allosteric Models (case study 1) HIV Reverse Transcriptase
- 41. Allosteric Models (case study 1) Class Allosteric Compounds Orthosteric Compounds ROC (OOB) Sensitivity Specificity PPV NPV MCC HIV RT 1,933 1,204 1.00 0.90 0.94 0.95 0.87 0.83
- 42. Allosteric Models (case study 1) Property Importance (Accuracy) Importance (Gini) Correlation 'Allosteric’ Structure O Count Frac 0.05 133.97 -0.47 Molecular PolarSurfaceArea 0.05 85.44 -0.37 CM#FCFP_6#885225145 0.04 70.80 0.37 AromaticBonds Frac 0.04 52.19 0.36 H_Acceptors Frac 0.03 54.14 -0.43 RotatableBonds_Frac 0.03 35.21 -0.30 RingBonds_Frac 0.02 29.05 0.38 Molecular Fractional PolarSurfaceArea 0.02 34.23 -0.40 ALogP 0.02 42.45 0.27
- 43. Allosteric Models (case study 2) Class Allosteric Compounds Orthosteric Compounds ROC (OOB) Sensitivity Specificity PPV NPV MCC Protein Kinase B 248 755 1.00 0.91 0.99 0.97 0.97 0.23
- 44. Allosteric Models (case study 2) Property Importance (Accuracy) Importance (Gini) Correlation 'Allosteric’ Structure Molecular SASA 0.05 48.18 0.75 Num Bonds 0.03 38.03 0.75 Molecular SurfaceArea 0.02 23.86 0.74 Molecular Volume 0.01 14.07 0.74 CM#FCFP_6#-874404860 0.01 6.20 0.78 Num RingAssemblies 0.01 7.75 0.03 AromaticBonds Frac 0.01 4.67 -0.60 CM#FCFP_6#266887156 0.01 16.73 0.28
- 45. Allosteric Models (case study 3) Class Allosteric Compounds Orthosteric Compounds ROC (OOB) Sensitivity Specificity PPV NPV MCC Adenosine Receptors 697 9177 0.99 0.92 0.98 0.80 0.99 0.84
- 46. Allosteric Models (case study 2) Property Importance (Accuracy) Importance (Gini) Correlation 'Allosteric’ Structure Heteroatom Frac 0.01 104.93 -0.34 CM#FCFP_6#-1617833330 0.01 79.21 0.59 Average BondLength 0.01 28.96 0.21 Molecular Weight 0.01 10.24 -0.08 Molecular PolarSurfaceArea 0.01 12.05 -0.15 Molecular Volume 0.01 7.44 -0.08 Molecular SurfaceArea 0.01 9.08 -0.11 Molecular SASA 0.01 6.94 -0.09
- 47. Current work • Finalizing all models and sets ▫ To be distributed with paper • Scaffold and monomer profiling (ongoing) ▫ Allosterically biased versus non-allosterically biased • Retrieving missed primary literature on allosteric modulators • Application of models to: ▫ Compound libraries (allosteric-like libraries) ▫ HTS hit lists
- 48. What makes a compound an allosteric modulator? Physicochemical profiling of allosteric regulators of proteins Gerard JP van Westen Anna Gaulton John P Overington