Chapter 2
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Validation of Reaction Vectors for de Novo Design Dimitar Hristozov,*,1 Michael Bodkin,1 Beining Chen,2 Hina Patel,3 and Valerie J. Gillet3 1Eli
Lilly UK, Erl Wood Manor, Windlesham, Surrey GU20 6PH of Chemistry, University of Sheffield, Western Bank, Sheffield S10 2TN 3Department of Information Studies, Regent Court, 211 Portobello St., University of Sheffield, Western Bank, Sheffield S1 4DP *E-mail:
[email protected] 2Department
A detailed validation of a new de novo design algorithm for the in silico generation of synthetically accessible compounds is presented. The algorithm is based on reaction vectors which describe the changes that take place at a reaction centre and which have been extracted from a knowledge-base of reactions. In the de novo design context, novel chemical compounds are generated by applying the reaction vectors to new starting materials. Here the algorithm is validated by attempting to reproduce a large number of diverse chemical reactions. On average, 90% of the reactions investigated (ranging from functional group interconversions to complex rearrangements) were successfully reproduced, thus showing the general applicability of the proposed algorithm.
Introduction Virtual screening has become commonplace in drug discovery with computational techniques such as similarity searching and protein-ligand docking routinely used to predict the bioactive properties of molecules. However, these techniques are usually applied to databases of compounds which have already been synthesised which therefore limits the novelty that can be accessed. De novo design, on the other hand, refers to the design of previously unknown © 2011 American Chemical Society In Library Design, Search Methods, and Applications of Fragment-Based Drug Design; Bienstock, R.; ACS Symposium Series; American Chemical Society: Washington, DC, 2011.
Downloaded by DUKE UNIV on May 2, 2012 | http://pubs.acs.org Publication Date (Web): September 30, 2011 | doi: 10.1021/bk-2011-1076.ch002
compounds to fit a set of constraints, for example, to fit into the binding site of a target protein or to fit to a pharmacophore derived from known active compounds (1). De novo design is appealing since it provides a way of discovering novel compounds of therapeutic potential. However, chemical space is enormous (it has been estimated that up to 1060 compounds could exist with 90% and 90% and
