1 Cheminformatics David Shiuan Department of Life Science and Institute of Biotechnology National Dong Hwa University

2 Cheminformatics Application of computational tools to solve discovery chemistry problems such as structural and chemical data, library design, and virtual screening. Requires a chemical information system 1. Effective storage of structures and data 2. Accurate retrieval of structures 3. Calculation of structure-derived data such as physical properties and 3D-conformation 4. Execution of in silico chemistry operations Applied Bioinformatics Jun 3, 2008

3 The first step Choose a chemical structure model. The structures generated by this model need to be standardized, easily interpreted by a computer, compact, and ideally human readable.

4 The Second Step Appropriate mechanisms are available to retrieve structures that match a target structure or pattern in a variety of ways as in the following examples. Target structure: Cytosine NC1=NC(=O)NC=CC1 Target pattern: Oxygen or nitrogen [N,O]C1=NC(O)=NC=C1 Substituted pyrimidine; Match structure:

5 Lastly Ability to execute various in silico operations on registered compounds. For example, the ability to perform a reaction transform on a set of compounds as illustrated below. [H][N:4]([H])[C]. [C:1](=[O:2])[Cl]  [C:1](=[O:2])[N :4]([H])[C].[Cl][H] Amine + Acid chloride  Amide

6 Representations of Chemical Structure

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8 SMILES (Simplified Molecular Input Line Entry Specification)

9 SMILES Specification Rules 1. Atoms Atoms are represented by their atomic symbols: this is the only required use of letters in SMILES

10 SMILES Specification Rules 2. Bonds Single, double, triple, and aromatic bonds are represented by the symbols -, =, #, and :, respectively. Adjacent atoms are assumed to be connected to each other by a single or aromatic bond (single and aromatic bonds may always be omitted).

11 SMILES Specification Rules 3. Branches ( ) Branches are specified by enclosing them in parentheses, and can be nested or stacked

12 SMILES Specification Rules 4. Cyclic Structures Cyclic structures are represented by breaking one bond in each ring

13 SMILES Specification Rules Disconnected compounds are written as individual structures separated by a "." (period). 5. Disconnected Structures

14 Chemical Database Available Chemical Directory (ACD) ~28 萬 ZINC (UCSF) >460 萬 (3D formatted database, by UCSF, since 2005) MayBridge >6 萬 (3D formatted database, by the company) MedChem Beilstein >900 萬 (the largest database for organic chemistry since 1771, now maintained by Elsevier) World Drug Index (WDI) World of Molecular Bioactivity (WOMBAT) Toxic Substance Control Act (TSCA) >14 萬

15 Database Size

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35 Acta Crystallographica D60 (2004)

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40 JME Molecular Editor © is a Java program which allows to draw, edit, and display molecules and reactions. JME editor is relatively small (37 kB) what assures fast loading. For non-commercial use, the JME editor is available free of charge directly from peter.ertl [at] novartis.com.

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49 Welcome to the Interactive 2D to 3D Molecular Converter and Viewer at Molsoft, LLC

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54 ODA (Optimal Docking Areas) a new method to predict protein-protein interaction sites on protein surfaces