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.

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. 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. 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

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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. National Institutes of Health
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Lipinski C, Hopkins A (2004) Nature 432:855–861.
Chemical space

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U.S. Department of Health and Human Services6

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Locate chemical
of interest

8. National Institutes of Health
U.S. Department of Health and Human Services8
Locate chemical
of interest Optimization,
define analogue,
replacement, ….

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, ….

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U.S. Department of Health and Human Services10
Drug repurposing
Locate chemical
of interest Optimization,
define analogue,
replacement, ….
Investigate ADME/Tox
properties

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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

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U.S. Department of Health and Human Services12
Investigate
new area

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U.S. Department of Health and Human Services13
Efficient navigation tool

14. 14
Google Maps

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Google Maps approach
• Interactive
• Easy to use
• Informative
• Responsive
• ….
Chemical space

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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/

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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

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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

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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

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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. www.chemmaps.com
version 1.0
ACS New Orleans (March 2018)

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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. 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

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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

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Live demo (video)

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Future Vision
• Project a all map on the fly

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Future Vision
• Select option on the map
• Project a map on the fly

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Future Vision
• Select option on the map
• Compute distances between several chemicals using
various metrics
• Project a map on the fly

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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. National Institutes of Health
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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

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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. Fourches’ lab
Dr. Denis Fourches
NIEHS
Dr. Nicole Kleinstreuer
Office of Data Science
Dr. Kamel Mansouri
(contractor, ILS)

33. www.chemmaps.com
@SpaceChemMaps

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Annexes

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EnvMap: projections
Principal component analysis
216 descriptors
PC1=14%, PC2 = 11%, PC3 = 9%
Independent component
analysis

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
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
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
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)

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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

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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
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
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

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Projection
z = 78 3D descriptors
x, y = 138 1D-2D descriptors
Multiple PCA
PC1: 13%
PC2: 9%
PC3: 24%
Coverage of variance

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Future Vision: Environmental Maps

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Future Vision: Environmental Maps
• Define and project several domains

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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. 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)

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Future Vision: map on the fly
• Define new map on the fly
• Chemical databases
• Precomputed coordinates
• Local version

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Future Vision: Virtual reality

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Future Vision: Navigation

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Future VisionFuture Vision: Navigation
• Project new chemical lists on map
• Add your chemicals/data/model predictions on the map

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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

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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