PubChem: An Open Repository for Chemical Structure and Biological Activity Information Steve Bryant The NIH Biowulf Cluster: 10 Years of Scientific Supercomputing February 3, 2009

… NIH “Molecular Libraries” … Basic design / approach … Current discovery tools / example … Planned discover tools … New discovery tools ? PubChem Overview …

NIH Molecular Libraries Program … Molecular Libraries Screening Centers Network (MLSCN) Compound Repository (MLSMR) Instrumentation Chemical Diversity Assay Development Predictive ADMET Technology Development Screening Informatics Cheminformatics Research Centers

Molecular Libraries BioAssays … Investigator Customized Assay Screen Hit picking, confirmation, secondary screens Hit List Optimization Chemistry Compound Repository Assay Peer review

Molecular Libraries Components …

MLSCN Created … 2005

MLPCN Created … 2008

… NIH “Molecular Libraries” overview … Basic design / approach … Current discovery tools / example … Planned discover tools … New discovery tools ? PubChem Overview …

… “GenBank model” … direct depositions by investigators … highly automated (low database cost) … 25 year precedents in biology … less precedent in chemical biology PubChem Approach …

Growth In PubChem Contributing Organizations

… Contributed substance records … with chemical structure … chemical names and comments … links to contributor web sites … contributed links to other NCBI biomedical databases PubChem Contents …

Growth In PubChem Substances / Compounds

PubChem Standardization...

… Contributed bioassay records … with assay description / protocol … links to tested substances … summary and detailed test results … links to contributor web sites and other NCBI databases PubChem Contents …

Growth In PubChem BioAssays

Growth In PubChem Tested Substances

… NIH “Molecular Libraries” overview … Basic design / approach … Current discovery tools / example … Planned discover tools … New discovery tools ? PubChem Overview …

… Optimize “discoverability” for molecular biologists by integrating PubChem into NCBI’s Entrez / PubMed Search Engine … Chemical structure search … Bioassay result search … Structure-activity tools PubChem Retrieval System …

NCBI’s Entrez Search Engine...

Entrez Links and Neighbors... Protein Sequences Protein 3D Structure Activity Profile Similarity PubChem Small Molecules PubMed Literature Bioactivity Screens VAST Structure Similarity Term Frequency Statistics Chemical Structure Similarity 2,000,000 users... 60,000,000 hits... … per day Target Sequence Similarity

PubChem Users per Day

Search for “Shoichet inhibitors”...

PubMed Article Retrieved...

Link to PubChem Records...

“Kaempferol” in PubChem...

Similar Compounds in PubChem...

“Quercetin” in PubChem...

Compare Protein / Ligand Complexes...

Link to Another Structure...

Tyrosine Kinase Family Member...

Links from “Quercetin” to PubMed...

PubMed Records...

Links from Quercetin to BioAssays...

BioAssay records...

BioAssay where “Active”...

Entrez Links and Neighbors... Protein Sequences Protein 3D Structure Activity Profile Similarity PubChem Small Molecules PubMed Literature Bioactivity Screens VAST Structure Similarity Term Frequency Statistics Chemical Structure Similarity 2,000,000 users... 60,000,000 hits... … per day Target Sequence Similarity

… Optimize “discoverability” for molecular biologists by integrating PubChem into NCBI’s Entrez / PubMed Search Engine … Chemical structure search … Bioassay result search … Exploratory structure-activity tools PubChem Retrieval System …

Compounds Similar to Quercetin...

PubChem Bioactivity Analysis...

PubChem Structure-Activity...

Active Compound Cluster...

BioAsay Cluster...

Another BioAssay Cluster...

PubMed Connection...

PubChem Structure-Activity...

… NIH “Molecular Libraries” overview … Basic design / approach … Current discovery tools / example … Planned discover tools … New discovery tools ? PubChem Overview …

… Bottom-line “Summaries” of multi-step Molecular Libraries screens … “Chemical Reagent” links for gene and protein records when possible … Add 3D-conformer similarity to structure-activity analysis … Support multi-target “panel” screens Planned Discovery Tools …

“Quercetin” in PubChem...

“Quercetin” Similar Conformers...

… NIH “Molecular Libraries” overview … Basic design / approach … Current discovery tools / example … Planned discover tools … New discovery tools ? PubChem Overview …

Systems-biology “pathway” links among chemical biology screens / results … Links to bioactivity information derived from scientific literature, literature abstraction, and other sources … New Discovery Tools ?

“Quercetin” in PubChem...

“Quercetin” NLM Toxicology...

“Quercetin” NLM Toxicity...

Evan Bolton Jie Chen Svetlana Dracheva Lewis Geer Lianyi Han Jane He Siqian He Karen Karapetian Vahan Simonyan Ben Shoemaker Wenyao Shi Tugba Suzek Paul Thiessen Valery Tkachenko Jiyao Wang Yanli Wang Jewen Xiao Jian Zhang