Maximising drug hits

Exploiting chemical diversity for drug discovery   

M Entzeroth and P A Bartlett   

Cambridge, UK: Royal Society of Chemistry  2006 | 345pp | ?119.95 (HB) | ISBN 0 85404 842 1 

Reviewed by Christopher Newton

This book is authored by 39 contributors and reviews the contemporary hit discovery process. Surveyed are the sources of chemicals for screening - particularly how large numbers of compounds can be acquired efficiently - and how the biological attributes of those compounds can be generated in both cost- and time-efficient ways. 

Modern chemical techniques that reduce the costly need to purify synthetic arrays of molecules are presented to the reader in the early chapters (solid-phase reagents, microwaves, sonochemistry and fluorous chemistry). Less familiar territory covers the production of molecules for screening by genetically altering enzymes that produce compound classes like polyketides, or by diversifying from natural product scaffolds. The book is, however, typical of its era and largely ignores new natural products as sources of new hits.  

The book provides useful comparisons of commercial sources of compounds. For organisations wedded to the requirement to obtain molecules with ’diversity’, introductions to this concept are given, and indeed for the computational diversity specialist, mathematical tools are derived. For organisations more interested in acquiring molecules likely to interact with genomic classes, the derivation of such molecules is usefully reviewed. For the generalist, the characteristics of drug-likeness - the fraction of the chemical universe likely to give exposure after oral administration - is well covered. 

The remaining nine chapters of the book deal with processing molecules to generate biological data. Included are the technical problems of handling very small volumes of liquids so that reproducible biological results can be generated. Technologies for screening are reviewed across the chapters; some get a chapter to themselves (fluorescence screening, NMR screening). Assessment of molecules in vitro and in silico for in vivo pharmacokinetics and liabilities is reviewed, and the later hit and lead optimisation phase of in-depth compound characterisation by high-content screening is also surveyed. 

I am currently responsible for the chemical and biological operations of a company that generates large numbers of compounds and their associated biological data for clients worldwide, and I thought that this book might be a useful companion for an 11 hour trip to Japan. The anticipation was largely rewarded, as the authors give sensible, contemporary views of the issues surrounding generating and testing large numbers of compounds in the hit-finding process.