NCBI Pub Chem Workshop Pub Chem Webpage http

NCBI Pub. Chem Workshop Pub. Chem Webpage: http: //pubchem. ncbi. nlm. nih. gov/ Pub. Chem Workshop Webpage: http: //www. ncbi. nlm. nih. gov/Class/Pub. Chem/course. htm TOPICS: Pub. Chem What it is and How to Search it Searching with Structures: Structural Similarity & Structure Clustering Analysis Bio. Assay Database Information: Activity Analysis Structure–Activity Relationships: SAR Analysis September 21, 2007 Pub. Chem—Substance, Compound, Bio. Assay

Pub. Chem Mission The NIH Molecular Libraries Roadmap High-throughput and large-scale screening efforts with small molecules to study the functions of genes, cells and biochemical pathways. This is based on: Ø Accessible Human Genome Project Data Ø Combinatorial Library Research & Development (methods, compounds and databases) Ø High-Throughput Screening Methodologies (robotic technology and informatics) Goal: To develop new ways to explore the functions of genes and signaling pathways in health and disease and facilitate the development of new drugs. Pub. Chem—Substance, Compound, Bio. Assay

Pub. Chem Mission The Molecular Libraries Roadmap has three components: 1. Molecular Libraries Small Molecule Repository & Screening Center Network: The MLSMR was developed to be a central molecule repository containing substances that will be analyzed via high-throughput screening assays by a consortium of small-molecule screening centers (MLSCN). 2. Technology Development: With new assay R&D applied by the MLSCN, the ultimate goal is to catalog a comprehensive set of small molecule modulators of the genes and functions of humans and other organisms. 3. Cheminformatics: NCBI’s Pub. Chem Database was developed as a new and comprehensive database of chemical structures and their biological activities, as well as added links to other NCBI biological databases and the Pub. Med scientific literature database. Pub. Chem—Substance, Compound, Bio. Assay

The National Center for Biotechnology Information Bethesda Created in 1988 as a part of the National Library of Medicine at NIH Ø Ø Establish public databases Research in computational biology Develop software tools for sequence analysis Disseminate biomedical information Pub. Chem—Substance, Compound, Bio. Assay

http: //www. ncbi. nlm. nih. gov Text Entrez Sequence BLAST Protein Structure VAST Small Molecule Structure Pub. Chem Structure Search Pub. Chem—Substance, Compound, Bio. Assay

http: //pubchem. ncbi. nlm. nih. gov/search/ Data Analysis Tools: Differential display of data via structure clustering, structureactivity heat maps and customizable result retrieval tables. http: //pubchem. ncbi. nlm. nih. gov/assaycluster. cgi Pub. Chem—Substance, Compound, Bio. Assay

Pub. Chem Databases Primary Databases: information is provided, updated and “owned” by Submitters. § Composed of Substances which may be of known or unknown composition and also may contain a discrete compound or mixtures of compounds. § Submitters add “Hard” links to Pub. Chem Bio. Assay records and outside sources. Hydrolyzed feathers Diphenhydramine Citrate Aspartame § Composed of Experimental data with Derivative Database: information is provided, updated and “owned” by NCBI. § Composed of discrete compounds with known chemical structure. § Summary reports about the known chemical compounds described in Pub. Chem Substance. § Addition of Automated Links which are combined from information provided on Pub. Chem Substance & Bio. Assay records. Background, Protocols and Results for bioactivity screens of chemical substances described in Pub. Chem Substance § Submitters add “Hard” links to Pub. Chem Substance records and outside sources. Cell-line Growth Effectors HIV Infectivity Pyruvate Kinase Estrogen Receptor Binding Pub. Chem—Substance, Compound, Bio. Assay

Pub. Chem Overview Pub. Chem Substance: 19, 599, 664 substances Molecular Libraries Screening Center Network & NIH Substance Repository Theoretical Properties Zinc, Chem. DB, NIST Biological Properties Chem. Bank Pub. Chem Compound: Protein 3 D Structures MMDB 10, 938, 543 compounds Toxicology Chem. IDplus 545, 627 have been assayed Imaging Agents MICAD, MOLI Journal Publishers Thompson Pharma Metabolic Pathways BIND, Biocyc, (KEGG) Substance Vendors Sigma-Aldrich Chemical Reactions Boston University Center for Chemical Methodology and Library Development (CMLD-BU) Pub. Chem Bio. Assay: 604 assays of 1, 709, 112 substances Molecular Libraries Screening Center Network: NIH Chemical Genomics Center Columbia DTP/NCI Emory Scripps Southern Research Institute Structural Genomics Consortium University of New Mexico Penn Center for Molecular Discovery University of Pittsburgh San Diego Center for Chemical Genomics Vanderbilt Screening Center for GPCRs, Ion Channels and Transporters Pub. Chem—Substance, Compound, Bio. Assay

Structure of Bio. Assay Records Pub. Chem—Substance, Compound, Bio. Assay

Structure of a Substance Record Pub. Chem—Substance, Compound, Bio. Assay

NCBI’s Pub. Chem Compounds What we do: Standardization of Structures Chemical Data Verification ◦ ◦ ◦ Atom description (label, element) Functional group clean-up Atom valence verification to prevent non-sense structures “Normalize” and “Standardize” ◦ ◦ Valence-Bond canonicalize (for Tautomer invariance) Aromaticity detection and selfconsistency Stereochemistry detection Explicit hydrogen assignment Structural Representation ◦ ◦ 2 D Coordinate generation Images created Me. SH is NLM’s controlled vocabulary used for indexing articles for MEDLINE/Pub. Med. Me. SH terminology provides a consistent way to retrieve information that may use different terminology for the same concepts. Calculation and Addition of Information Nomenclature ◦ IUPAC ◦ SMILES & SMARTS ◦ In. Ch. I Structural Information ◦ Calculate & store “Fingerprints” ◦ Calculate & link to similar structures (90% level) Physical Properties ◦ Molecular Formula ◦ Molecular Weight ◦ Number of H-bonds donor/acceptor sites ◦ XLog. P value ◦ Lipinski value (bioavailability) ◦ Number of Rotatable bonds Links to NCBI Database Records ◦ Structures (MMDB records) ◦ Protein sequences (from Structure links) ◦ Genes (from Protein links) Links to Me. SH Terms through IUPAC name Then we “Index” the records! Pub. Chem—Substance, Compound, Bio. Assay

Structural, Stereochemical & Nomenclature Standardization Substance as Deposited Validated & Standardized Compound Pub. Chem—Substance, Compound, Bio. Assay

Structural, Stereochemical & Nomenclature Standardization CID: 450 CID: 11616093 CID: 5757 IUPAC: 13 -methyl 6, 7, 8, 9, 11, 12, 14, 15, 16, 17 decahydrocyclopenta[a]phenant hrene-3, 17 -diol IUPAC: (8 R, 9 S, 13 S, 14 S, 17 S)2, 4, 16, 17 -pentadeuterio 13 -methyl-6, 7, 8, 9, 11, 12, 14, 15 octahydrocyclopenta[a]phenanthre ne-3, 17 -diol IUPAC: (8 S, 9 S, 13 S, 14 S, 17 S)13 -methyl 6, 7, 8, 9, 11, 12, 14, 15, 16, 17 decahydrocyclopenta[a]phenanth rene-3, 17 -diol SMILES: CC 12 CCC 3 C(C 1 CCC 2 O)CCC 4 =C 3 C=CC(=C 4)O SMILES: [2 H]C 1=CC 2=C(CC[C@@H]3[C@ @H]2 CC[C@]4([C@H]3 CC([C@]4 ([2 H])O)([2 H])C)C(=C 1 O)[2 H] SMILES: C[C@]12 CC[C@H]3[C@H]([C@ @H]1 CC[C@@H]2 O)CCC 4=C 3 C=CC(=C 4)O Compound Pub. Chem—Substance, Compound, Bio. Assay

NCBI’s Pub. Chem Compounds What we do: Standardization of Structures Chemical Data Verification ◦ ◦ ◦ Atom description (label, element) Functional group clean-up Atom valence verification to prevent non-sense structures “Normalize” and “Standardize” ◦ ◦ Valence-Bond canonicalize (for Tautomer invariance) Aromaticity detection and selfconsistency Stereochemistry detection Explicit hydrogen assignment Structural Representation ◦ ◦ 2 D Coordinate generation Images created Me. SH is NLM’s controlled vocabulary used for indexing articles for MEDLINE/Pub. Med. Me. SH terminology provides a consistent way to retrieve information that may use different terminology for the same concepts. Calculation and Addition of Information Nomenclature ◦ IUPAC ◦ SMILES & SMARTS ◦ In. Ch. I Structural Information ◦ Calculate & store “Fingerprints” ◦ Calculate & link to similar structures (90% level) Physical Properties ◦ Molecular Formula ◦ Molecular Weight ◦ Number of H-bonds donor/acceptor sites ◦ XLog. P value ◦ Lipinski value (bioavailability) ◦ Number of Rotatable bonds Links to NCBI Database Records ◦ Structures (MMDB records) ◦ Protein sequences (from Structure links) ◦ Genes (from Protein links) Links to Me. SH Terms through IUPAC name Then we “Index” the records! Pub. Chem—Substance, Compound, Bio. Assay

Examples of Linking in Entrez Term frequency statistics Structure Similarity Pub. Med Pub. Chem 3 -D Bio. Assay Structure Pub. Chem Substance Activity Profile Structure Similarity Pub. Chem Compound Sequence Similarity (BLASTp) Structure Similarity (VAST) Protein Sequences Pub. Chem—Substance, Compound, Bio. Assay

Structure of Substance & Compound Records Emory U MLSC NCGC DTP/NCI MLSMR SMID PDSP NIAID EPA DSSTox Ch. EBI MMDB Chem. IDplus Chem. Bank ZINC BIND Lipid. MAPS Prous Science Drugs of the Future Nature Chemical Biology Cambridge. Soft Corporation KEGG Thomson Pharma Discovery. Gate Oestergon Syndiol Estrifam estrol Tradelia Oestradiol Vagifem Estroclim evex Climara Ovahormon Altrad Estrogen D-Estradiol Divigel Ovasterol Evorel Extrasorb 17 beta. Estring Ovastevol Dihydromenform Oesclim Femanest Oestradiol Ovocyclin on Femestrol Polyestradiol Vivelle cis-Estradiol Perlatanol SK-Estrogens Fempatch Zerella Dihydrofolliculin Zumenon Profoliol Theelin, dihydro-Gelestra Trocosone Dermestril Ginedisc Amnestrogen Encore Ovocycline Aerodiol Gynestrel Combipatch Menest Corpagen Climaderm Microdiol Oestradiolum Systen Gynergon Compudose Oestrogel Progynon DH Oestrogynal Estraderm Primofol Progynon-DH Ovociclina Alora Pub. Chem—Substance, Compound, Bio. Assay Estrogel Bardiol Estreva Dihydroxyoestrin. Activella Femogen Menorest estradiol-17 beta Estraderm TTS Femtran

Direct Links to Additional Information Emory U MLSC NCGC DTP/NCI MLSMR SMID PDSP NIAID EPA DSSTox Ch. EBI MMDB Chem. IDplus Chem. Bank ZINC BIND Lipid. MAPS Prous Science Drugs of the Future Nature Chemical Biology Cambridge. Soft Corporation KEGG Thomson Pharma Discovery. Gate Pub. Chem—Substance, Compound, Bio. Assay

Entrez Indexing & Searching Hints Field Delimiters term 1 term 2 term 1[limit] OP term 2[limit] OP …… where: Limits Preview/Index History limit = Entrez indexing field in square brackets OP = AND, OR, NOT (Boolean operators must be in all CAPS!) Wildcards: estrogen[synonym] vs. estrogen*[synonym] Ranges: 120: 250[MW] Complex queries: Record Structures Downloading data chemidplus[Source. Name] AND 300: 500[MW] NOT (ca[Element] OR fe[Element]) Pub. Chem—Substance, Compound, Bio. Assay

Setting Limits Compound & Substance Bio. Assay Pub. Chem—Substance, Compound, Bio. Assay

Preview/Index: Finding & Choosing Terms Pub. Chem—Substance, Compound, Bio. Assay

History: Customized, Stored Databases —Entrez keeps track of all of your searches. — You can “concatenate” searches with ANDs, ORs, NOTs. Or you can purposefully store searches for later use, for example: A Compound or Substance A set of Compounds or Substances: Bio. Assay tab link (those in the search that were assayed) Me. SH term structures link (those with an assigned function) Similar Structures link A Bio. Assay A set of Bio. Assays: similar Bio. Assays that tested the same compound Pub. Chem—Substance, Compound, Bio. Assay

Entrez Doc. Sum Pages Pub. Chem—Substance, Compound, Bio. Assay

Direct Links to Additional Information Pub. Chem—Substance, Compound, Bio. Assay

New Link to Me. SH/Pub. Med Searches Pub. Chem—Substance, Compound, Bio. Assay

Downloading Bio. Assay Records Downloading the data Pub. Chem—Substance, Compound, Bio. Assay

Downloading Substance & Compound Records Emory U MLSC NCGC DTP/NCI MLSMR SMID PDSP NIAID EPA DSSTox Ch. EBI MMDB Chem. IDplus Chem. Bank ZINC BIND Lipid. MAPS Prous Science Drugs of the Future Nature Chemical Biology Cambridge. Soft Corporation KEGG Thomson Pharma Discovery. Gate Downloading the data: Pub. Chem—Substance, Compound, Bio. Assay

Downloading Bulk Data Searching Hints Record Structures Downloading data from Entrez Doc. Sum Pages Estradiol[synonym] Pub. Chem—Substance, Compound, Bio. Assay

Accessing the Data in Bulk Pub. Chem—Substance, Compound, Bio. Assay

Help for Programmers NCBI Toolbox: In-house source code useful for incorporating NCBI-like functionality into their programs. Three main parts: Data Model, Data Encoding and Programming Libraries. Examples: BLAST, Cn 3 D, Sequin, Data format conversion scripts http: //www. ncbi. nlm. nih. gov/IEB/Tool. Box/index. cgi E-Utilities: Guidelines for Entrez “URL calls” used to access data. Designed for use in scripts. Examples: ESearch, EPost, ESummary, EFetch and ELink http: //www. ncbi. nih. gov/entrez/query/static/eutils_help. html Caution: Overuse may result in blocked IPs! Pub. Chem—Substance, Compound, Bio. Assay

- Guided Example - Practice Problems http: //www. ncbi. nlm. nih. gov/Class/Pub. Chem/course. html Essentials Pub. Chem—Substance, Compound, Bio. Assay

Intermission TOPICS: Pub. Chem What it is and How to Search it Searching with Structures: Structural Similarity & Structure Clustering Analysis Bio. Assay Database Information: Activity Analysis Structure–Activity Relationships: SAR Analysis Pub. Chem—Substance, Compound, Bio. Assay