PubChem and Its Applications for Drug Discovery

Lehigh Univ., Apr. 26, 2019
URL: https://pubchem.ncbi.nlm.nih.gov

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Introduction to PubChem

 PubChem (https://pubchem.ncbi.nlm.nih.gov)
 A “public” repository of information on small molecules
and their biological activities, developed and
maintained by the U.S. National Institutes of Health
(NIH).
 Launched in 2004 as a part of the Molecular Libraries
Roadmap initiatives.
 A key resource of chemical information for researchers
in the area of cheminformatics, chemical biology,
medicinal chemistry, and many others.

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Jan
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Oct
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Oct
Jan
NumberofUsers
(millions)
Month
Number of Monthly Unique Users
(Jan 2015 - Mar 2019, interactive users only)
2017
PubChem Usage Statistics
2015 2016
3.5 million unique users per month at peak (October 2018)
2018
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2019

Top 5 Chemistry Websites
1. acs.org
2. rsc.org
3. sigmaaldrich.com
4. pubchem.ncbi.nlm.nih.gov
5. cas.org
Source: https://www.alexa.com/topsites/category/Top/Science/Chemistry
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PubChem is the only public website among them.

 Dual role of PubChem
>600
Data
sources
PubChem The public
 Data archive/repository:
Collects/maintains chemical information submitted by data
contributors.
 Knowledgebase:
Provides (high-quality) data to the public.

Depositor-provided
Bioactivity test results
Unique chemical
structure extraction
through
Standardization
Depositor-provided
substance descriptions
Unique chemical structures
Activity of
tested
“substances”
Activity of “compounds”
derived from associated
“substances”
Data Contributors
Substance
deposition
Assay
deposition
 Data organization in PubChem

 PubChem (https://pubchem.ncbi.nlm.nih.gov)
 PubChem contains:
• >243.9 million substance descriptions,
• >97.6 million unique chemical structures,
• >264.8 million biological activity test results,
• >1.3 million biological assays, covering >10,000 unique
protein sequence targets.
(Arguably) the largest corpus of
publicly available chemical information
from 600+ data sources.
(as of April 24, 2016)

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Exploring PubChem
using the web interfaces

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Note
 (Almost) all tasks you can do using PubChem’s web
interfaces can be automated using its programmatic
interfaces.

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PubChem Web Interfaces
 Text Search
 Structure Search
 ID List Upload
 Classification Browser
 PubChem Docs

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URL: https://pubchem.ncbi.nlm.nih.gov

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 Text Search
 ID List Upload
 PubChem Docs

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 Text Search
 ID List Upload
 PubChem Docs

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 Text Search
 ID List Upload
 PubChem Docs

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Structure
download
Refine
the result

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 Text Search
 ID List Upload
 PubChem Docs

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PubChem for
Drug Discovery

 PubChem’s chemical space
Lipinski’s rule of 5
(drug-likeness)
Congreve’s rule of 3
(lead-likeness)
Lead
compounds
Drug
candidates
Modification
Mol. Wt.: < 500
H-Bond Donor ≤ 5
H-Bond Accepter ≤ 10
LogP ≤ 5
Mol. Wt.: < 300
H-Bond Donor ≤ 3
H-Bond Acceptor ≤ 3
LogP ≤ 3
Rotatable Bond ≤ 3
PSA ≤ 60

Lead-like
11.2 millions
(11%)
Drug-like
73.3 millions
(75%)
All compounds
97.6 millions
(100%)

Ro5
73.3
millions
(75%)
Ro51
15.0
millions
(15%)
Ro52
6.5 millions
(7%)
Ro53
1.3 millions
(1%)
Ro54
0.3 millions
(~0%)
Ro5 + Ro5-1 = 90%

 Bioactivity Data in PubChem
Tested
3.4 millions
(3.50%)
Active
(AC  1 nM)
62 thousands
(0.06%)
Active
(1 nM < AC  1 M)
713 thousands
(0.73%)
Active
(others)
465 thousands
(0.47%)
Inactive
2.1 millions
(1.34%)
Not Tested
94.2 millions
(96.51%)
All Compounds
97.6 millions
(100.00%)

High-Throughput
Screening data
Literature-extracted
data

High-Throughput
Screening data
• From Molecular Libraries
Program and other HTS
projects.
• Many inactives
• False hits
(e.g., aggregators,
autofluoresent
compounds)
• Often measured at single
concentration
data

High-Throughput
Screening data
• From Molecular Libraries
Program and other HTS
projects.
• Many inactives
• False hits
(e.g., aggregators,
autofluoresent
compounds)
• Often measured at single
concentration
data
• From manual curation or
data mining
• No (or few) inactives
• Provided by various
PubChem depositors
including:
ChEMBL,
PDBbind, BindingDB,
Guide to Pharmacology

• Manual extraction from peer-reviewed papers in journals in
medicinal chemistry and natural product
ChEMBL
• Experimental binding affinity data for biomolecular
complexes in the PDB
PDBBind
• Binding affinities, focusing chiefly on the interactions of
protein considered to be drug targets with drug like small
molecules
BindingDB
• Drug targets (G-protein-coupled receptors, ion channels, and
nuclear hormone receptors and their ligands
Guide to Pharmacology
 Literature-extracted Bioactivity data

 Annotations available in PubChem
 DrugBank
 Comprehensive information on FDA-approved and
investigational drugs
• drug indications,
• mechanism of action,
• target macromolecules,
• interactions with genes/proteins,
• ADMET, ……
 Hazardous Substance Data Bank (HSDB)
 Toxicological information on chemicals of interest
in environmental and human health

 Molecular Modeling Database (MMDB)
 Protein-bound 3D structures (found in PDB)
 Cambridge Structural Database (CSD)
 3-D crystal structures
 NLM’s Dailymed
 Drug labeling information

 FDA
 Orange book
 Unique ingredient identifiers,
 Pharmacologic Classes
 EPA
 Substance Registry Services
 Chemical data collected under the:
o Toxic Substance Control Act
o Clean Air Act

 Availability of compounds for subsequent
experiments
• Virtual screening hits should be synthesizable or
purchasable.
• PubChem contains “real” molecules (not “virtual”
molecules)
• At least one or more data contributors claim that
they have the compound and/or information about
it.
• Some of these data contributors are chemical
vendors (e.g., Sigma Aldrich).

 Two important aspects of PubChem records
(in the context of “compound availability”)
 Non-live compounds:
 Not searchable although they exist.
 No associated substances due to:
o Mistakenly submitted substances
o Incorrect information
o No intention to share

 Two important aspects of PubChem records
(in the context of “compound availability”)
 Non-live compounds:
 Not searchable although they exist.
 No associated substances due to:
o Mistakenly submitted substances
o Incorrect information
o No intention to share
 Legacy designation:
 No longer maintains their records up-to-date.
o Discontinued funding, low business priority, …

 Compound patentability for IP protection
• PubChem provides patent link information for
compounds, provided by:
o IBM
o SureChEMBL (formerly, SureChem)
o NextMove Software
o SCRIPDB
o BindingDB

 Compound patentability for IP protection
>336 million chemical-patent links
>6 million patent documents
>16 million unique chemical structures
• Covering patent documents published by:
o U.S. Patent and Trademark Office (PTO)
o European Patent Office (EPO)
o World Intellectual Property Organization (WIPO)
 Compounds with patent links are annotated with
WIPO International Patent Classification (IPC)
information

Entrez Utilities
(E-Utils)
Power User
Gateway
(PUG)
PUG-SOAP
PUG-REST
PubChem
RDF REST
PUG-View
 Programmatic access to PubChem for
Automation of VS pipeline

 Conceptual Framework of a PUG-REST request
PubChem
Servers
User’s
Computer
① INPUT
Identifiers
(CIDs, SIDs, AIDs)
③ OUTPUT
Results in
a desired format
② OPERATION
with identifiers
 All necessary information is encoded into a one-line URL.

Options specific to
some operations
http://pubchem.ncbi.nlm.nih.gov/rest/pug/<INPUT>/<OPERATION>/<OUTPUT>[?OPTIONS]
Prolog
(common to all PUG REST requests)
<INPUT>
Specifies identifiers of interest,
by identifiers
by chemical name
by chemical structure search
by cross reference
by listkey, ......
<OPERATION>
Specifies what to do with input
get full records
get molecular properties
get synonyms or images
get cross references
many other operations
<OUTPUT>
Specifies desired output format
XML  PNG
JSON  SDF
JSONP  CSV
ASNB  TXT
ASNT
 URL construction for a PUG-REST request
http://...... /compound/cid/2244,1983/record/XML?record_type=3d
 Retrieve in XML full records for CIDs 2244 and 1983, including 3-D
structure description.
 All necessary information is encoded into a one-line URL.

Request volume limitations
 PUG-REST is NOT designed for very large volumes of
requests
(e.g. millions of requests)
 Any script or application should not make more than five
requests per second to avoid overloading the PubChem
servers.
 If you have a large data set to process, please contact us
for help on optimizing your task.

 PubChemRDF
 Encodes PubChem information using RDF.
 Helps researchers work with PubChem data on local
computing resources using semantic web technologies.
 harnesses ontological frameworks to help facilitate
PubChem data sharing, analysis, and integration with
resources external to the National Center for
Biotechnology (NCBI) and
across scientific domains.
RDF = Resource Description Framework

 Programmatic access to PubChem RDF data is also available
through a REST-ful interface.
 PubChemRDF for data exchange and integration
PubChemRDF
From FTP
Triple Store
Apache Jena TDB,
Open-Link
Virtuoso,
……
RDF-aware
graph
Databases
Neo4j, …
SPARQL
Query
Interface
Graph
Traversal
Algorithm
(RDF : Resource Description Framework)

59
Summary

 Summary
• PubChem is the largest source of publicly
available chemical information, collected from
more than 600 data sources.
• In addition to bioactivity data generated through
high-throughput screenings, PubChem contains a
substantial amount of bioactivity information
extracted from scientific articles.
• Chemical vendor and patent information for
compounds in PubChem helps prioritize hit
compounds for further screening.

 Summary
• PubChem supports programmatic access to its
data, allowing for building an automated virtual
screening pipeline.
• PubChemRDF allows users to download
PubChem data on a local computing facility and
integrate them with their own data.
• PubChem data can be used for developing
computational prediction models for bioactivity or
toxicity of molecules.

 References
 Getting the most out of PubChem for virtual screening
Expert Opin. Drug Discov. 2016, 11(9), 843-855.
 PubChem 2019 update: improved access to chemical data
Nucleic Acids Res (2019) 47(D1):D1102-1109.
 PubChem Substance and Compound Databases
Nucleic Acids Res (2016) 44 (D1): D1202-D1213.
 An update on PUG-REST: RESTful interface for programmatic
access to PubChem
Nucleic Acids Res (2017) 46 (W1): W563-570.
 PUG-SOAP and PUG-REST: web services for programmatic access
to chemical information in PubChem
Nucleic Acids Res (2015) 43 (W1): W605-W611

Acknowledgements
 The PubChem Team
 Funding from the National Library of Medicine
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 PubChem data contributors and users
Evan Bolton Jia He Thiessen Paul
Jie Chen Siqian He Bo Yu
Tiejun Chung Qingliang Li Leonid Zaslavsky
Asta Gindulyte Ben Shoemaker Jian Zhang

Thank you for your attention.
Questions?
Email: sunghwan.kim@nih.gov
kimsungh@ncbi.nlm.nih.gov

PubChem and Its Applications for Drug Discovery

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