Preface [Hot Topic: Bead Technologies and Post-Genomic Drug Discovery (Guest Editor: Gerard Rosse)]

Both the completion of the Human Genome Project and the sequencing of the genetic codes of microorganisms are providing the unique opportunity to understand Life better and consequently are producing a vast number of potential targets for therapeutic intervention. There is a great need for novel, intelligent strategies for identifying valid targets and discovering druglike leads against them. This Special Issue provides an overview of bead technologies in the everyday practice of drug research. Bead technologies are defined here as a broad term covering combinatorial chemistry approaches based on polymer beads (e.g. solidphase synthesis, polymer supported reagents, on bead assays, etc.). Drug discovery proceeds as a multi-stage process from the identification of a potential therapeutic target through lead generation, lead optimization to clinical testing before a drug product is marketed. The first series of reviews are focused on the application of bead technologies at the very early stage of drug discovery, namely genomics and proteomics. A single polymer bead can be considered as a miniaturized reactor which is carrying a chemical entity and in which a biological assay can be performed. The application of a multiplexed bead-based assay is described in the first review of this collection by Yingyongnarongkul, How, Diaz-Mochon, Muzerelle and Bradley. They provide a comprehensive review of the role of beadbased assays for high-throughput screening, gene expression, single nucleotide polymorphism and genomic analysis. The review of Groth, Renil and Meinjohanns focuses on techniques based on biocompatible polymers and combining both high throughput organic synthesis and high throughput screening in one process. In the fields of chemical genetics and chemogenomics, chemical entities are exploited to identify and characterize proteins and to understand the cellular processes in which they operate. In groundbreaking work in this area, Eguchi, McMillan, Nguyen, Teo, Chi, Henderson and Kahn describe the concept of peptide secondary structural mimetics within chemogenomics. In a broader review of the subject, Thorpe summarizes the application of compound arrays generated from solid-phase chemistries to the field of forward and reverse chemical genetics. The selection of a therapeutic target is followed by the identification and optimization of lead structures. The synthesis of combinatorial libraries is today well recognized as a successful approach to generate novel chemical entities for the identification of new leads. The next series of review articles demonstrate the importance of solid-phase organic synthesis to generate libraries. The review of Goodnow, Guba and Haap focuses on design approaches to deliver small molecule libraries that will increase the success of lead optimization. The concept of chemical biology applied to a target family is explored in the review of Park and Kimmich, in which chemical libraries directed for protein kinases are described. Natural products have been one of the major sources of leads and drugs. In their review Knepper, Gil and Braese discuss the synthesis of complex molecules derived from natural products using solid-phase synthesis or chemistries assisted by polymer-bound reagents (one other component of bead technologies). Pulici, Cervi, Martina and Quartieri provide comprehensive coverage of a relatively new area of organic chemistry - multicomponent and domino reactions performed on solid-phase. In another variation of solidphase organic synthesis, Michalek, Horn, Tzschucke and Bannwarth describe the use of catalysts non-covalently bound to the polymer. The mechanisms of organic reactions on a solid support are not well understood, and the difficulties of transferring chemistry from solution to solid phase have discouraged many chemists. The final review by Schroeder provides perspectives on the application of NMR methods to monitor reaction steps and describe the interpretation and validation of the structures of complex molecules while attached to polymer beads. I would like to acknowledge the scientists for their excellent contributions and the experts that helped review the manuscripts for this issue. This collection of reviews, mini-reviews and research articles was assembled to illustrate the critical significance of bead technologies along the value chain of the drug discovery process. Considering the many uses of such techniques, we can expect the development of exciting new approaches and applications in the coming years.