Lead generation is a critical early phase of drug discovery that takes place once a biological target of therapeutic interest has been identified. High throughput screening (HTS) is currently the most widely used technology for delivering initial active molecules (hits) suitable for evaluation and subsequent refinement through medicinal chemistry. HTS has led to a range of development compounds and marketed drugs. Other screening methodologies, established and emerging, include virtual library design and screening, fragment-based screening approaches (e.g. NMR, high-throughput X-ray crystallography, mass spectroscopy), structure-based rational design, and targeted library generation. Screening hits are shaped into lead series by processes that may include structure minimization to reveal the active pharmacophore. This is followed by structure expansion to refine biological potency and selectivity, and physicochemical, absorption, distribution, metabolism, and excretion (ADME) properties.
Educational Session: From Chemistry to the Clinic: Pathways for Drug Discovery and Development: Part 1: Early Discovery and Lead Generation

Efficient and parallel lead discovery by high-throughput kinase profiling; Patrick Zarrinkar. Ambit Biosciences, San Diego, CA

The virtual kinome: The impact of computational methods on lead discovery and optimization; Jack A. Bikker. Wyeth Research, Pearl River, NY

Fragment-based drug discovery; Stephen W. Fesik. Abbott Laboratories, Abbott Park, IL,