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ChemMaps version 2, ACS Orlando 2019

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Easily navigating chemical space has become more important due to the increasing size and diversity of publicly-accessible databases such as DrugBank, ChEMBL, or DSSTox, and associated high-throughput screening (HTS) and other datasets. Modelers typically rely on complex projection techniques using molecular descriptors computed for all the chemicals to be visualized. However, the multiple cheminformatics steps required to prepare, characterize, compute and explore those molecules, are technical, typically necessitate scripting skills, and thus represent a real obstacle for non-specialists. Inspired by the popular Google Maps application, we developed the ChemMaps.com webserver to easily navigate chemical spaces.
The first version of ChemMaps.com was developed to browse and visualize the space of 2,000 FDA-approved drugs and over 6,000 drug candidates based on the DrugBank database (https://www.drugbank.ca/) and was extended on ~47,000 environmental chemicals. In this new version, the chemical coverage has been extended to include the full DSSTox inventory (>700,000 chemicals and additional browsing, searching, and exporting/importing options were updated and developed. Users can now upload their own set of chemicals and visualize them on the available maps and/or define a new map from them. All computed data, e.g. coordinates, chemical descriptors, etc. can now be downloaded. Different navigation options have been also developed, including a distance computing on the fly for two selected chemicals and a faster and more responsive environment.). Users can search for specific compounds, overlay regulatory classification and labeling based on animal toxicity data, explore and export nearest neighbor space, refine the projections based on physicochemical properties, and link out to the EPA’s CompTox Dashboard (https://comptox.epa.gov/dashboard) for detailed information on a chemical. Work is ongoing to embed ChemMaps.com on the EPA’s CompTox Dashboard to provide real-time chemical space visualization specific to the compound of interest.
Borrel,A. et al. (2018) Exploring drug space with ChemMaps.com. Bioinformatics, 1–3.

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ChemMaps version 2, ACS Orlando 2019

  1. 1. Alexandre Borrel, PhD Postdoctoral Research Fellow, National Institute of Environment Health Sciences, RTP, North Carolina, USA Exploring the Chemical Universe using www.ChemMaps.com @AlBorrel0000-0001-6499-4540
  2. 2. National Institutes of Health U.S. Department of Health and Human Services2 More than 1.1060 accessible molecules 1,2,3 (1) Hann, M.M., and Oprea, T.I. (2004). Curr. Opin. Chem. Biol. 8: 255–263. (2) Ursu, O., Rayan, A., Goldblum, A., and Oprea, T.I. (2011). Rev. Comput. Mol. Sci. 1: 760–781. (3) Drew, K. L. M., Baiman, H., Khwaounjoo, P., Yu, B., & Reynisson, J. (2012). Journal of Pharmacy and Pharmacology, 64(4), 490–495. Introduction
  3. 3. National Institutes of Health U.S. Department of Health and Human Services3 More than 1.1060 accessible molecules 1,2,3 (1) Hann, M.M., and Oprea, T.I. (2004). Curr. Opin. Chem. Biol. 8: 255–263. (2) Ursu, O., Rayan, A., Goldblum, A., and Oprea, T.I. (2011). Rev. Comput. Mol. Sci. 1: 760–781. (3) Drew, K. L. M., Baiman, H., Khwaounjoo, P., Yu, B., & Reynisson, J. (2012). Journal of Pharmacy and Pharmacology, 64(4), 490–495. Introduction
  4. 4. National Institutes of Health U.S. Department of Health and Human Services4 Chemical space: “…Chemical space’ is a term often used in place of ‘multi- dimensional descriptor space’: it is a region defined by a particular choice of descriptors…” Dobson CM (2004) Nature 432:824–828 Chemical space
  5. 5. National Institutes of Health U.S. Department of Health and Human Services5 Lipinski C, Hopkins A (2004) Nature 432:855–861. Chemical space
  6. 6. National Institutes of Health U.S. Department of Health and Human Services6
  7. 7. National Institutes of Health U.S. Department of Health and Human Services7 Locate chemical of interest
  8. 8. National Institutes of Health U.S. Department of Health and Human Services8 Locate chemical of interest Optimization, define analogue, replacement, ….
  9. 9. National Institutes of Health U.S. Department of Health and Human Services9 Investigate ADME/Tox properties Locate chemical of interest Optimization, define analogue, replacement, ….
  10. 10. National Institutes of Health U.S. Department of Health and Human Services10 Drug repurposing Locate chemical of interest Optimization, define analogue, replacement, …. Investigate ADME/Tox properties
  11. 11. National Institutes of Health U.S. Department of Health and Human Services11 Define, visualize domains Locate chemical of interest Optimization, define analogue, replacement, …. Investigate ADME/Tox properties Drug repurposing
  12. 12. National Institutes of Health U.S. Department of Health and Human Services12 Investigate new area
  13. 13. National Institutes of Health U.S. Department of Health and Human Services13 Efficient navigation tool
  14. 14. 14 Google Maps
  15. 15. 15 Google Maps approach • Interactive • Easy to use • Informative • Responsive • …. Chemical space
  16. 16. 16 DrugMap: compounds ~8,000 drug entries (release 12-2018): • ~2,500 FDA-approved small molecule drugs • Over 5,000 experimental drugs. https://www.drugbank.ca/
  17. 17. 17 DrugMap: descriptors https://www.drugbank.ca/ RDkit: http://www.rdkit.org/ PaDEL: http://www.yapcwsoft.com/dd/padeldescriptor/ 1D descriptors: chemical formula 2D descriptors: connectivity 3D descriptors: spatial coordinates (ligprep to generate 3D) C23H34O5 • Molecular weight • Count of atoms • … • Pharmacophore based • … • Volume • Surface • … Descriptor selection: • Remove null variance • Person’s correlation coefficient < 0.9
  18. 18. 18 DrugMap: descriptors space Samples (Compounds) Variables (descriptors) X1 X2 ... X238 1 X1,1 X1,2 ... X1, 238 2 X2,1 X2,2 ... X2, 238 ... ... ... ... ... 8550 X8550,1 X8550, 2 ... X8550,238 116 1D/2D descriptors 122 3D descriptors
  19. 19. 19 PC1 = 14%; PC2=9%; PC3 = 26% • Sufficient coverage of variance • Understandable z = 70 3D descriptors x, y = 116 1D-2D descriptors Multiple PCA DrugMap: descriptors space
  20. 20. National Institutes of Health U.S. Department of Health and Human Services20 Environmental Chemical Space ~48,000 chemicals with 3D descriptors Informed by regulatory lists*: • Endocrine Disruptor Screening Program • Toxic Substances Control Act Inventory • Canadian Domestic Substances List • Swedish Chemicals Agency ~12,000 chemicals with acute systemic toxicity data • Rat oral LD50 values • GHS/EPA classifications *not inclusive https://comptox.epa.gov/dashboard/
  21. 21. www.chemmaps.com version 1.0 ACS New Orleans (March 2018)
  22. 22. National Institutes of Health U.S. Department of Health and Human Services22 www.ChemMaps.com ~30,000 unique users since March 2018 (ACS - New Orleans) ~1,000 new users each month (~ 8,000 in June 2018) @SpaceChemMaps
  23. 23. National Institutes of Health U.S. Department of Health and Human Services23 Challenges for version 2 • Extended universe: Distributed Structure-Searchable Toxicity (DSSTox) Database (EPA – EPA comptox) • > 800,000 chemicals, (chemical infrastructure for EPA’s Safer Chemicals Research, including the ToxCast and Tox21 high- throughput toxicology efforts) https://www.epa.gov
  24. 24. National Institutes of Health U.S. Department of Health and Human Services24 ChemMaps v2 work-in-progress • Extended universe: Distributed Structure-Searchable Toxicity (DSSTox) Database (EPA comptox dashboard) • > 800,000 chemicals • chemical infrastructure for EPA’s Safer Chemicals Research, including ToxCast and Tox21 high-throughput toxicology efforts • OPERA model predictions https://comptox.epa.gov/dashboard • More interactive • Users can input their data • Customizable • Accessibility
  25. 25. National Institutes of Health U.S. Department of Health and Human Services25 Live demo (video)
  26. 26. National Institutes of Health U.S. Department of Health and Human Services26 Future Vision • Project a all map on the fly
  27. 27. National Institutes of Health U.S. Department of Health and Human Services27 Future Vision • Select option on the map • Project a map on the fly
  28. 28. National Institutes of Health U.S. Department of Health and Human Services28 Future Vision • Select option on the map • Compute distances between several chemicals using various metrics • Project a map on the fly
  29. 29. National Institutes of Health U.S. Department of Health and Human Services29 Conclusions • www.chemmaps.com (version 2) • Project the whole DSSTox database • Update DrugBank (release 12-2018) • Customize the map • Upload chemical on the fly • Accessibility
  30. 30. National Institutes of Health U.S. Department of Health and Human Services30 Conclusions • www.chemmaps.com (version 2) • Project the whole DSSTox database • Update DrugBank (release 12-2018) • Customize the map • Upload chemical on the fly • Accessibility Requirements • Multiplatform (phone, tablet, computer) • Firefox >59, Chrome >65, Safari >5 (WebGL technology) • 1GB on GPU memory
  31. 31. National Institutes of Health U.S. Department of Health and Human Services31 Conclusions • www.chemmaps.com (version 2) • Project the all DSSTox database • Update drugbank (release 12-2018) • Customize the map • Upload chemical on the fly • Accessibility Requirements • Multiplatform (phone, tablet, computer) • Firefox >59, Chrome >65, Safari >5 (WebGL technology) • 1GB on GPU memory Beta version on the NIEHS network Release for the end of April 2019 @SpaceChemMaps
  32. 32. Fourches’ lab Dr. Denis Fourches NIEHS Dr. Nicole Kleinstreuer Office of Data Science Dr. Kamel Mansouri (contractor, ILS)
  33. 33. www.chemmaps.com @SpaceChemMaps
  34. 34. National Institutes of Health U.S. Department of Health and Human Services34 Annexes
  35. 35. National Institutes of Health U.S. Department of Health and Human Services35 EnvMap: projections Principal component analysis 216 descriptors PC1=14%, PC2 = 11%, PC3 = 9% Independent component analysis
  36. 36. 36 Principal component analysis 186 descriptors PC1=16%, PC2 = 11%, PC3 = 8% Independent component analysis 186 descriptors Multidimensional-scaling 3D 186 descriptors Euclidian distance DrugMap: projections
  37. 37. 37 DrugMap: compounds MolVS (RDkit): - SMILES standardization, normalize - Remove salts - Remove hydrogen - Remove fragments (mixture) 8,752 SMILES MolVS: https://molvs.readthedocs.io/en/latest/ Fourches,D. et al. (2016). J. Chem. Inf. Model., 56, 1243–1252. 8,551 canonical SMILES
  38. 38. 38 DrugMap: compounds MolVS (RDkit): - SMILES standardization, normalize - Remove salts - Remove hydrogen - Remove fragments (mixture) 8,752 SMILES 8,551 canonical SMILES C[S@@](=O)CC[C@H](N)C(O)=O DB02235 C[S+]([O-])CCC(N)C(=O)O DB02165 [Zn2+] …. MolVS: https://molvs.readthedocs.io/en/latest/ Fourches,D. et al. (2016). J. Chem. Inf. Model., 56, 1243–1252.
  39. 39. 39 DrugMap: descriptors space https://www.drugbank.ca/ RDkit: http://www.rdkit.org/ 1D descriptors: chemical formula 2D descriptors: connectivity C23H34O5 • Molecular weight • Count of atoms • … • Pharmacophore based • … 1D/2D RDKit descriptors (648)
  40. 40. 40 DrugMap: 3D generation RDkit: http://www.rdkit.org/ https://www.schrodinger.com/ligprep Riniker, S.; Landrum, G. A. J. Chem. Inf. Comp. Sci. 55:2562-74 (2015) 3D generations • Riniker and Laundrum (RDKit) SMILES SDF
  41. 41. 41 DrugMap: 3D descriptors Cao,D.-S. et al. (2013) J. Chem. Inf. Model., 53, 3086–3096 3D descriptors: spatial coordinates • Volume • Surface • Charge distribution • … 3D PyDPI descriptors (420)
  42. 42. 42 DrugMap: descriptors space Samples (Compounds) Variables (descriptors) X1 X2 ... X1068 1 X1,1 X1,2 ... X1,1068 2 X2,1 X2,2 ... X2,1068 ... ... ... ... ... 8550 X8550,1 X8550, 2 ... X8550,1068
  43. 43. 43 DrugMap: descriptors space Samples (Compounds) Variables (descriptors) X1 X2 ... X1068 1 X1,1 X1,2 ... X1,1068 2 X2,1 X2,2 ... X2,1068 ... ... ... ... ... 8550 X8550,1 X8550, 2 ... X8850,1068 Descriptor selection: • Remove null variance • Pairwise Person’s correlation coefficient < 0.9
  44. 44. National Institutes of Health U.S. Department of Health and Human Services44 Projection z = 78 3D descriptors x, y = 138 1D-2D descriptors Multiple PCA PC1: 13% PC2: 9% PC3: 24% Coverage of variance
  45. 45. National Institutes of Health U.S. Department of Health and Human Services45 Future Vision: Environmental Maps
  46. 46. National Institutes of Health U.S. Department of Health and Human Services46 Future Vision: Environmental Maps • Define and project several domains
  47. 47. National Institutes of Health U.S. Department of Health and Human Services47 Future Vision: Environmental Maps • Define and project several domains • Add entire DSSTox Inventory (>700,000 chemicals)
  48. 48. National Institutes of Health U.S. Department of Health and Human Services48 Future Vision: Environmental Maps • Define and project several domains • Add entire DSSTox Inventory (>700,000 chemicals) • Incorporate diverse biological datasets (e.g. ToxRefDB, HTT)
  49. 49. National Institutes of Health U.S. Department of Health and Human Services49 Future Vision: map on the fly • Define new map on the fly • Chemical databases • Precomputed coordinates • Local version
  50. 50. National Institutes of Health U.S. Department of Health and Human Services50 Future Vision: Virtual reality
  51. 51. National Institutes of Health U.S. Department of Health and Human Services51 Future Vision: Navigation
  52. 52. National Institutes of Health U.S. Department of Health and Human Services52 Future VisionFuture Vision: Navigation • Project new chemical lists on map • Add your chemicals/data/model predictions on the map
  53. 53. National Institutes of Health U.S. Department of Health and Human Services53 Future VisionFuture Vision: Navigation • Select and redefine part of the chemical map on the fly • Project new chemical lists on map • Add your chemicals/data/model predictions on the map
  54. 54. National Institutes of Health U.S. Department of Health and Human Services54 Future Vision : Navigation • Select and redefine part of the chemical map on the fly • Compute distances between several chemicals using various metrics • Project new chemical lists on map • Add your chemicals/data/model predictions on the map • Download area and matrix of distance

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