Lead Discovery and Lead Modification

Abstract

Abstract Chapter 2 focuses, in detail, on the many considerations encountered in lead discovery and lead modification stages of modern rational drug design, as typically practiced in pharmaceutical companies and many academic research laboratories. Examples emphasize how the concepts of organic chemistry are applied during the practice of these key stages of drug discovery. Major topics of discussion are the various sources for lead compounds, including virtual screening, computational methods, and fragment-based approaches, and desired properties of lead compounds. This is followed by an exploration of the objectives, considerations, and methods for subsequently optimizing lead compounds across multiple parameters such as potency, selectivity, and {ADME} properties. Approaches for the identification of the pharmacophore and for the determination of structure-activity relationships, including quantitative and other computational and molecular graphics-based methods, are discussed, and properties important to oral bioavailability and membrane permeability are described.