Editorial [Hot Topic: Chemical and Biological Integrity in HTS (Guest Editor: Gilles H. Goetz)]

While innovation, scientific expertise, business flair and leadership vision clearly are important factors in the success of a pharmaceutical company as it strive to create new medicines, a pharmaceutical company's most valuable asset may prove to be its compound screening libraries. Maintaining and growing these libraries in order to facilitate timely and effective high throughput screening campaigns is a challenging responsibility, This challenge generally falls upon "Material Management" or HTS groups and their work is crucial to screening success. Challenges that "Material Management" or HTS groups must address include determining criteria for deciding which compound should be included in the library. Selection can be based on combinatorial chemistry libraries, medicinal chemistry intermediates, and even natural products extracts, purified natural products, etc... The goal is to provide high quality, chemically diverse, reproducible chemical matter for biological screening and ultimately lead matter for medicinal chemistry. Structural integrity has to be assessed, including solution state, hydration level, and concentration of screening banks. Decisions have to be made in order to determine when to make such assessments. Structural evaluation can be performed at submission, at regular intervals throughout the compound library's live cycle, or exclusively after activity was detected by HTS. They must also address at which stage of HTS a compound should be considered for such assessment. At the primary level? After activity confirmation? Or after dose response determination (i.e. IC50)? In this Issue of Combinatorial Chemistry & High Throughput Screening, we have an exciting collection of contributions illustrating ways to generate, assess, QC and interpret data used to address the issues listed above. Edward Kerns (Wyeth) and colleagues extensively reviewed the recent literature describing the use of the most up to date analytical techniques (such as LC-MS, ELSD, CLND, etc...) for assessing compound integrity in an HTS environment. Bernard Choi (Merck) and coworkers focused their paper on an approach to rapidly process and interpret LC-MS data, based on a computer application developed in-house to process LC-MS report files containing both spectral and chromatographic data. Mark Strege (Lilly) and colleagues discuss the added value of the use of MS-MS, ELSD and CLND coupled with the bioassay-guided fractionation, or "biofractionation" technique where an activity profile correlates with a chromatographic profile. Richard Ellson (Labcyte) and coworkers discuss a new acoustic method of assessing water content in DMSO solutions (a major contributor to sample instability in solution) in storage plates. Michelle Kelly (Pfizer) and colleagues discuss the adverse effects of water uptake and freeze-thaw cycles on compound solubility in DMSO and demonstrate how one can re-solubilize a precipitated DMSO screening stock solution by low energy sonication. Ulrich Schopfer (Novartis) and coworkers describe a unique strategy used for addressing compound stability and solubility issues for HTS compound storage. Unsuitable compounds being excluded upfront, storage occurs at 4°C/20% relative humidity in a DMSO/water mixture, thus avoiding freeze-thaw cycles, and compounds are resolubilized at regular intervals. Ramesh Padmanabha (Bristol-Myers Squibb) and colleagues concentrated their effort on the process of HTS with an emphasis on quality control, reducing the variability of all the processes that have an impact on the final result. George Harrigan and Gilles Goetz (Pfizer) reviewed the current trends in Natural Products screening, including chemical screening, virtual screening , NP based library design. It has been a privilege reading those excellent pieces of work dedicated to help us find out "what is in our wells" in a preview atmosphere, but it is now time for prime-time release, therefore, enjoy.