Lewis D Pennington, Julia M Clay, Sandrine M Hell, Matthew J Hesse, Elizabeth V Jones, Rory C McAtee, Theodore D Michels, Alshaima'a M Qunies
Property-based drug design has advanced considerably since its emergence following the publication of the rule-of-5 in 1997. We show in this perspective that the classical bioisosteric exchange of an aromatic methine group with a nitrogen atom has broad utility in the modern context of drug multiparameter optimization. We also demonstrate how the "necessary nitrogen atom" can be leveraged for holistic property-based drug design, and include a historical overview, key concepts, and real-world case studies.