Chemoinformatics Harno Dwi Pranowo Prof Dr Chemistry Department

Chemoinformatics Harno Dwi Pranowo, Prof. Dr. Chemistry Department FMIPA UGM

Computation Oracle Database (HTS) All the compounds pass the Compounds were tested against related assays and showed activity, including selectivity within target families Lipinksi Rule of Five and toxicity filters Excel Spreadsheet (Toxicity) One of the compounds was previously tested for toxicology and was found to have no liver toxicity Oracle Database (Genomics) have been tested in a microarray assay Computation Several of the compounds had been followed up in a previous project, and solubility problems prevented further development Journal Article SCIENTIST The information in the structures and known activity data is good enough to create a QSAR model with a confidence of 75% Word Document (Chemistry) ? None of these compounds A recent journal article “These compounds look promising from their HTS results. Should I commit some chemistry resources to following them up? ” reported the effectiveness of some compounds in a related series against a target in the same family External Database (Patent) Word Document (Marketing) Some structures with a A report by a team in similarity > 0. 75 to these appear to be covered by a patent held by a competitor Marketing casts doubt on whether the market for this target is big enough to make development cost-effective

THREE BROAD TECHNOLOGIES ARE DRIVING DRUG DISCOVERY • Study of both structural and functional aspects of the genome, including both genes and proteins, leading to a greater understanding of cellular processes and disease GENOMICS Supported by BIOINFORMATICS • Rapid and systematic generation of a variety of molecular entities, or building blocks, in many different or unique combinations 3 CATALYTIC/ COMBINATORIAL CHEMISTRY HIGH THROUGHPUT SCREENING • Use of robotic automation to allow for massive parallel experimentation and testing of many compounds or targets

“A chemoinformatician is a machine …. . …” 4

From chemical documentation to chemoinformatics • Chemical documentation is long established – Chemisches Journal started in 1778 – Chemical Abstracts started in 1907 • First computer-based information systems and services in Sixties – Chemical Titles in 1961 – Morgan and Sussenguth algorithms in 1965 • Recent emergence of chemoinformatics – M. Hann and R. Green (1999), Chemoinformatics - a new name for an old problem? , Curr. Opin. Chem. Biol. , Vol. 3, pp. 379 -383.

Chemoinformatics: definitions • “The use of information technology and management has become a critical part of the drug discovery process. Chemoinformatics is the mixing of those information resources to transform data into information and information into knowledge for the intended purpose of making better decisions faster in the area of drug lead identification and optimization” F. K. Brown (1998), Chemoinformatics: What is it and how does it impact drug discovery? , Ann. Reports Med. Chem. , Vol. 33, pp. 375 -384 • Take 1998 as the starting point for the bibliometric analyses • Many alternatives, e. g. Ø “Chemoinformatics is a generic term that encompasses the design, creation, organization, management, retrieval, analysis, dissemination, visualization and use of chemical information” G Paris (August 1999 ACS meeting), Ø “Chemoinformatics is the application of informatics methods to solve chemical problems” J. Gasteiger and T. Engels (2003), Chemoinformatics: a Textbook, Wiley-VCH.

Chemoinformatics hits on Google Dec 2005 348, 100 April 2005 125, 600 July 2000 723 Number of word occurrences on Google, Taken from http: //www. molinspiration. com/chemoinformatics. html

Chemoinformatics-What is it? • Use of computer and informational techniques, applied to a range of problems in the field of chemistry. • This in silico techniques are used in pharmaceutical companies in the process of drug discovery.

Frank Brown’s Definition • …the mixing of information resources to transform data into information and information into knowledge, for the intended purpose of making decisions faster in the arena of drug lead identification and optimisation. – Brown, F. K. “Chemoinformatics, what it is and how does it impact drug discovery. ” Annual Reports in Medicinal Chemistry, 1998, 33, 375 -384. 9

Chemoinformatics-What is it?

Chemoinformatics-What is it?

• Boundaries between bioinformatics and chemoinformatics are fluid – Both should be closely combined or merged to significantly impact biotechnology or pharmaceutical research Bajorath, Jürgen, Ed. Chemoinformatics: Concepts, Methods, and Tools for Drug Discovery. (Methods in Molecular Biology; 275) Humana Press: Totawa, NJ, 2004.

Chemical Informatics: the application of information technology to chemistry (not with a specific focus on drug discovery) Chemical informatics is the application of information technology to help chemists investigate new problems and organize, analyze, and understand scientific data in the development of novel compounds, materials, and processes.

Major aspects of chemical informatics – Information Acquisition: Methods for generating and collecting data empirically (experimentation) or from theory (molecular simulation) – Information Management: Storage and retrieval of information – Information Use: Data Analysis, correlation, and application to problems in the chemical and biochemical sciences

Chemometrics • Chemometrics – Application of statistical methods to chemical data and the derivation of relevant statistical models and descriptors – Increasingly difficult to distinguish between chemometrics and chemoinformatics

Dmitrii Ivanovich Mendeleev, 1834 -1907 Discoverer of the Periodic Table— An Early “Chemoinformatician” 16

Why Mendeleev? Faced with a large amount of data, with many gaps, Mendeleev: – Sought patterns where none were obvious, – Made predictions about properties of unknown chemical substances, based on observed properties of known substances, – Created a great visualization tool! 17

The Periodic Table of the Elements by Mark Winter 18

Molecular descriptors and chemical spaces • There are no generally preferred descriptor spaces. • Require to generate reference spaces for specific application on a case by case

Application of Cheminformatics in the Drug Industry • The computer is used to analyze the interactions between the drug and the receptor site and design molecules with an optimal fit. • Once targets are developed, libraries of compounds are screened for activity with one or more relevant assays using High Throughput Screening. 20

Application of Cheminformatics in the Drug Industry • Hits are then evaluated for binding, potency, selectivity, and functional activity. • Seeking to improve: – Potency – Absorption – Distribution – Metabolism – Elimination 21

Characteristics of a Chemical Informatics researchers • Appreciates the value of algorithms • Is interested in data mining, data modeling, and relational database systems • Pays attention to searching issues and the literature • Has compatibility and commonality with bioinformatics research • Is able to talk to computer scientists. 22

Major Journals • Journal of Chemical Information and Computer Sciences (ACS): to split in 2005 into: – Journal of Chemical Information and Modeling – Journal of Chemical Theory and Computation • Journal of Molecular Graphics and Modelling (Elsevier) • Journal of Combinatorial Chemistry (ACS) • Journal of Proteome Research (ACS) • Proteomics (Wiley-VCH) • Molecular and Cellular Proteomics (ASBMB) • Acta Crystallographica (IUCr) 23

Chemical Informatics Textbooks • Leach, Andrew R. ; Gillet, Valerie J. An Introduction to Chemoinformatics. Kluwer, 2003. ISBN 1 -4020 -1347 -7 • Gasteiger, Johann; Engel, Thomas. Chemoinformatics: A Textbook. Wiley-VCH, 2003. ISBN 3 -527 -30681 -1 • Bajorath, Jürgen, Ed. Chemoinformatics: Concepts, Methods, and Tools for Drug Discovery. (Methods in Molecular Biology; 275) Humana, 2004. ISBN 158829 -261 -4 24

Reference Works • Encyclopedia of Computational Chemistry, Schleyer, P. von R. ; Allinger, N. L. ; Clark, T. ; Gasteiger, J. ; Kollman, P. A. ; Schaefer, H. F. ; Shreiner, P. R. (Eds. ). 5 v. Wiley, Chichester, 1998. • Gasteiger, Johann J. , ed. Handbook of Chemoinformatics: From Data to Knowledge. 4 v. Wiley-VCH, 2003. ISBN 3 -527 -306803 • Reviews in Computational Chemistry. Wiley-VCH, 1990 • Paris, Greg. Bibliography: Chemical Information Retrieval and 3 D Searching. http: //panizzi. shef. ac. uk/cisrg/links/grep/chem. DB. 4. html • SIRCh: Chemical Informatics Home Page at Indiana University http: //www. indiana. edu/~cheminfo/informatics/cinformhome. html 25

Conclusion • Chemical Informatics is an evolving field with many facets. • It will become increasingly important in areas of chemistry outside the drug industry. • It will play an increasing role in the developing area of proteomics. 26

Open Source / Free Software • Blue Obelisk - http: //wiki. cubic. unikoeln. de/dokuwiki/doku. php • In. Ch. I - http: //www. iupac. org/inchi/ • JMOL – http: //jmol. sourceforge. net • FROWNS - http: //frowns. sourceforge. net/ • Open. Babel - http: //openbabel. sourceforge. net/ • CML - http: //cml. sourceforge. net/ • CDK - http: //almost. cubic. uni-koeln. de/cdk/ • MMTK http: //starship. python. net/crew/hinsen/MMTK/

Yahoo! Chemoinformatics Discussion List • For – – Job postings Ideas exchange Questions Industry – Student connections To join, go to http: //groups. yahoo. com/group/chemoinf Or send an email to chemoinf-subscribe@yahoogroups. com