Editorial [Hot topic: Medicinal Chemistry in the Pilot Phase of the Molecular Libraries Screening Center Network (Guest Editor: Donna M. Huryn)]

In 2005, the National Institutes of Heath (NIH) established the Molecular Libraries Screening Center Network (MLSCN). This initiative was a component of the NIH Roadmap for Medical Research [1], and hoped to build on the success of the Human Genome Project. In a simplistic analysis, if the human genome project addressed the question “what is the sequence of each protein in a human?”, the logical next question would be “what do each of the proteins these genes code for do?” To start to address this considerably complex question, the MLSCN aimed to generate a set of small molecule “tools” that could be used by biomedical researchers [2,3]. Ideally, these small molecule probes would be well characterized both chemically and biologically, the associated data would be publicly available through Pubchem [4], and samples of these “probes” would be made accessible to biomedical researchers. The definition of a “probe” considered potency, selectivity, physical properties such as solubility and permeability, accessibility and novelty, but was intentionally broad so as to encompass the diversity of targets and assays types that were imagined (e.g., isolated protein/ enzyme, cellular assays, phenotypic assays and whole organism assays). An essential criterion imposed was the concept that any probe should provide an improvement over any currently available tools (e.g., improved potency, selectivity, cell permeability etc.). The pilot phase of the program ran for three years, and resulted in the designation of over 50 probes. Reports describing these probes are available on the web-site: https://mli.nih.gov/mli/mlp-probes/. The value of these probes to the biomedical community will require their availability and use throughout the biomedical community, and will take some time to determine [5]. While the pilot phase of the program generated a number of probes [6], it also served to highlight some of the typical issues that are encountered in high throughput screening assay development and campaigns, and in hit-to-lead medicinal chemistry programs. These issues are well known in industry, less widely appreciated in academic laboratories, and perhaps even less often described in the scientific literature. Case studies from several of the laboratories that participated in the pilot phase of the MLSCN described in this issue exemplify the diverse projects that were pursued, the medicinal chemistry approaches and strategies applied, and some of the lessons learned. Perhaps one of the most important lessons learned was the value of medicinal chemistry in development of these probes.