An Integrated Approach to Fragment-Based Lead Generation:Philosophy, Strategy and Case Studies from AstraZenecas Drug Discovery Programmes

摘要: Fragment-based lead generation (FBLG) has recently emerged as an alternative to traditional high throughput screening (HTS) identify initial chemistry starting points for drug discovery programs. In comparison HTS libraries, the sets FBLG tend contain orders of magnitude fewer compounds, and compounds themselves are less structurally complex have lower molecular weight. This report summarises advent within industry then describes experience at AstraZeneca. We discuss (1) optimising design (2) hit detection methodologies, (3) evaluation quality use ligand efficiency calculations, (4) approaches evolve fragment-based, low complexity hits towards drug-like leads. Furthermore, we exemplify our with case studies in following areas: antibacterial enzyme targets, GPCRs (melanocortin 4 receptor modulators), prostaglandin D2 synthase inhibitors, phosphatase inhibitors (protein tyrosine phosphotase 1B), protease (b-secretase).