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ChemMaps talk at ACS New Orleans 2018

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The need for navigating the chemical space has become more important due to the increasing size and diversity of chemical biological databases (e.g., Chemspider, DrugBank, ChEMBL, Toxcast). To do so, modelers typically rely on projection techniques applied to series of quantitative molecular descriptors directly computed from two-dimensional chemical structures. However, the multiple cheminformatics steps required to visualize chemical space are technical, necessitate coding 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 was developed to browse and visualize the space of 2,000 FDA-approved drugs and over 6,000 drug candidates. Each compound was initially characterized using a large set of molecular descriptors including 1D-2D RDKIT descriptors and 3D PADEL descriptors (238 1D-2D and 44 3D after removing correlated descriptors). Principal Component Analysis was used to project compounds in three-dimensional space, where compounds’ coordinates in the first two dimensions were calculated using 1D-2D descriptors, and the third dimension (Z axis) was determined using 3D descriptors. To optimize the representation of the space and the interactive, user-friendly navigation experience, we developed the ChemMaps.com webserver using modern 3D-optimized web technologies such as HTML5, JavaScript, and CGI. The chemical coverage is now being expanded to include environmental chemical space based on the U.S. EPA TSCA inventory, as well as toxicological categorizations based on curated animal study data and predictive high-throughput screening signatures. Users accessing ChemMaps.com can immediately explore the entire compound library using a responsive, mouse-based, easy-to-use navigation tool. Since all information and coordinates are pre-computed, the browsing is instantaneous and does not require computational skills. Similar to searching Google Maps for a specific address, users can search the ChemMaps via a dedicated search bar (e.g., name, indications, pharmacological class, toxicity values) and visualize the space with options to zoom in on chemical “neighborhoods”. Additional browsing, searching, and exporting options are underway, including tools to support read-across and chemical risk assessment.

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ChemMaps talk at ACS New Orleans 2018

  1. 1. Alexandre Borrel, PhD Postdoctoral Research Fellow, National Institute of Environment Health Sciences, RTP, North Carolina, USA Exploring chemical space using ChemMaps.com @AlBorrel
  2. 2. 3/20/2018 2 Introduction More than 1.10 60 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.
  3. 3. 3/20/2018 3 Introduction More than 1.10 60 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.
  4. 4. 3/20/2018 4 Chemical space 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
  5. 5. 3/20/2018 5 Lipinski C, Hopkins A (2004) Nature 432:855–861. Chemical space
  6. 6. 3/20/2018 6 Efficient tool of navigation Chemical space
  7. 7. 3/20/2018 7 Google Maps
  8. 8. 3/20/2018 8 Google Maps approach • Interactive • Easy to use • Informative • Responsive • …. Chemical space
  9. 9. 3/20/2018 9 DrugMap: compounds ~11,000 drug entries (12-2017): • ~2,500 FDA-approved small molecule drugs • Over 5,000 experimental drugs. https://www.drugbank.ca/ Exclude inorganic compounds and long peptides ~8,000 chemicals projected
  10. 10. 3/20/2018 10 DrugMap: descriptors space 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
  11. 11. 3/20/2018 11 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
  12. 12. www.chemmaps.com
  13. 13. National Institutes of Health U.S. Department of Health and Human Services15 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/
  14. 14. National Institutes of Health U.S. Department of Health and Human Services16 Projection z = 78 3D descriptors x, y = 138 1D-2D descriptors Multiple PCA PC1: 13% PC2: 9% PC3: 24% Coverage of variance
  15. 15. National Institutes of Health U.S. Department of Health and Human Services18 Conclusions • Web based tool (three.js) • Easy to use • Publically accessible • Multiple platforms (mobile, tablet) • Including several navigation options (search bar, description panel, …) • Available for drug space and environmental chemical space (beta) www.chemmaps.com
  16. 16. National Institutes of Health U.S. Department of Health and Human Services19 Future Vision Ongoing: • Project new chemical lists on map • Select and redefine part of the chemical map on the fly • Add your chemicals/data/model predictions on the map • Compute distances between several chemicals Long-term: • Project your unique chemical space, choose from several projection methods and similarity search algorithms • Add entire DSSTox Inventory (>700,000 chemicals) • Define and project several domains • Virtual reality
  17. 17. Fourches’ lab Dr. Denis Fourches NIEHS Dr. Nicole Kleinstreuer Dr. Kamel Mansouri (contractor, Scitovation)
  18. 18. www.chemmaps.com
  19. 19. 3/20/2018 22 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
  20. 20. National Institutes of Health U.S. Department of Health and Human Services23 EnvMap: projections Principal component analysis 216 descriptors PC1=14%, PC2 = 11%, PC3 = 9% Independent component analysis

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