Molecular recognition: the fragment approach in lead generation

Abstract

The successful practice of medicinal chemistry is crucially dependent on the principles of molecular recognition: the first and "fundamental" requirement for a drug is to bind to its target; specificity, or at least selectivity, of binding is also a must. Subsequent optimization steps to develop a lead compound into a drug are a complex mixture of processes that are not yet fully understood or predictable. Fortunately, criteria exist to discard leads that would be intractable for optimization. The concepts of non-lead-likeness and lead-likeness, in respect to drug-likeness and non-drug-likeness, have prompted a rich discussion in the recent medicinal chemistry literature. The fragment approach is an emerging philosophy in the process of lead compound discovery. The basic interactions responsible for binding affinity are defined from the "protein interactions world" and key structural fragments are combined according to the criteria of three-dimensional diversity to find new leads. New techniques in screening are used for the detection of the weaker interactions of fragments with their targets that might be undetectable in classical biological assays.