Hit and lead generation: beyond high-throughput screening

Abstract

Due to the escalating downstream costs in the development phase, objective quality assessment of lead series long before entering clinical trials is an increasing necessity within pharmaceutical research. Moving away from the linear process of compound optimization towards a parallel strategy in which the profile of chemical entities is shaped in a multidimensional manner allows the properties of a molecule to be appropriately balanced in a rapid, iterative fashion. The initiating point in a medicinal chemistry programme can arise from a variety of sources. Depending on the target and further information available, they can range from brute-force, serendipity search-based methods to information-rich design approaches for identifying novel chemical entities for further optimization. High-throughput screening campaigns currently provide the main source for chemistry initiation in pharmaceutical research. Assay development time, logistical hurdles and issues concerning compound acquisition increasingly demand alternative approaches to complement this lead discovery pathway. The design of combinatorial compound libraries on the basis of predicted molecular properties is now widely applied, increasing the quality of the product compounds generated. In addition focused libraries can be generated on the basis of ligand or biostructural information most effectively enhanced by support from modern integrated computational and synthetic methods. Computational algorithms allow the annotation and grouping of biological targets as well as chemical structures. 'Chemogenomics' is the interface between disciplines where chemical topology space is married with biological target space. Chemogenomics databases will in future allow existing target-ligand information to be used prospectively to identify drugable targets and design tailored new ligand motifs thus creating valuable knowledge.