Preface [Hot topic: Hit-to-Lead: Driving Forces for the Medicinal Chemist (Guest Editor: Benoit Deprez and Rebecca Deprez-Poulain)]

HIT-TO-LEAD: DRIVING FORCES FOR THE MEDICINAL CHEMIST Drug discovery is a succession of design, synthesis and selection steps. The understanding at a molecular level of the biological processes underlying many diseases has lead to a miniaturization of the bioassays and a dramatic increase in throughput, at the initial step of selection. During the shift from animal testing to target-based assays much relevant information was lost for the medicinal chemist. Although activity data was easier to use and allowed quantitative-structure-activity relationships, they were also less relevant and even sometimes misleading. In the meantime, the increase in throughput of initial testing has also created a unprecedented demand for new compounds. To palliate this apparent shortage, combinatorial chemistry has been a the major source of leads. Mechanically, numbers had become a driving force not only for the screener but also for the chemist at the detriment of compound quality and druglikeness. Thus in the late '80s, better understanding of diseases has paradoxically disabled drug discovery. In the mid 90s it has been realized that numbers and pure diversity are not the only keys of success. The linear process whereby drug discovery started with the selection of compounds binding to the chosen target driven by affinity before animal testing has not been successful. The drug discovery process is now seen less linearly than previously. Discovery teams are now trying to optimize all possible inputs in concerted efforts: quality and (directed) diversity of compounds, as well as quality and diversity of information to drive changes in compound structure. The early identification of the most suitable active compound is now a common matter for chemists, molecular biologist and pharmacologists, who work in cross-disciplinary teams. One of the main tasks of hit-to-lead is to bridge the gap between on-target activity and efficacy in a whole organism. As exemplified by the meeting of the Medicinal Chemistry Division of the American Chemical Society in New Orleans (March 2003), hit-to-lead activities are clearly identified as a critical point in the drug discovery process. An important session of the meeting focused on of lead generation following high throughput screening. This issue tends to overview several key aspects of the chemical sciences underlying the success of hit optimization. Another strategy, described by Roger Crossley, relies on the design of targeted libraries using structural information of the target and statistical analysis of ligand binding data. Researchers from Biofocus apply the concept of informed diversity to the discovery of leads in the field of GPCRs. In another paper, Dragos Horvath from Cerep, describes the neighborhood behavior of bioactive compounds and rationalize the concept of similarity that underlies the work of every medicinal chemist in the course of hit optimization. Finally, Frank Landolt from Devgen develops the impact of early patenting of targets, screening methods and compounds in the drug discovery process, and especially at the hit-to-lead step. The techniques and concepts described in this issue, as well as related ones that could not been covered here, will surely provide valid hits from screening and reduce significantly hit-to-lead and hopefully hit-to-drug attrition.