The Evolving Druggability and Developability SpacePart One: DruggabilityPart Two: Developability

Part one: This review provides a holistic introduction to the evolving druggability and developability space. Before the genomic era when traditional druggable targets were the main stream of drug discovery, Lipinski’s rule-of-five (Ro5) evolved and served as a guide toward drug-like molecule design for oral delivery. In contrast, during the post-genomic era, a transition has occurred in discovery towards applying new chemistry to bind and modulate challenging biological targets for future innovative treatments. Consequently, drugging the yet-to-be drugged targets using various molecular modalities and discovery strategies is a key focus for drug discovery and development. Herein some of the changes arising during the discovery ‘druggability’ phase are described as well as their potential implications on overall developability. Part 1 discusses the general concepts of druggability and developability, the changes in target identification methods, the shifts in chemical space for new biological targets and finally the anticipated challenges arising from these transitions. Part Two: Herewithin is the second part of a two part publication on druggability and developability. This article provides a high-level evaluation of the current risks associated with physiochemical properties, ADME properties and formulation approaches for three classes of molecular modalities: complex small molecules, peptides/peptidomimetics, and oligonucleotides. An analysis of the strategies used to progress the most advanced candidate for each category is discussed. Finally, an outlook is provided detailing the trending chemistry and formulation strategies observed across these molecular modalities, which are directly related to their challenging physical-chemical properties.