A Review on the Role of Heterocyclic Scaffolds in Drug Discovery

Review Article

Abstract

Heterocyclic compounds form the structural core of a vast majority of therapeutic agents. Certain heterocyclic motifs, designated as "privileged structures," show a significant capacity to bind with high affinity to diverse biological targets. This versatility is often attributed to their rigid, defined 3D architectures, which present the main pharmacophoric elements (e.g., hydrogen bond donors/acceptors, aromatic/hydrophobic regions) in pre-organized spatial arrangements. These arrangements are frequently complementary to binding sites within large protein families, such as G protein-coupled receptors (GPCRs), kinases, and ion channels. The identification of these compounds has profoundly influenced medicinal chemistry, serving as validated starting points for the design of compound libraries and facilitating the exploration of chemical space around biologically relevant scaffolds. The current perspective extends beyond simple promiscuity; the focus is now on utilizing these core structures as templates for lead optimization, where subtle modifications at specific vectors can steer binding affinity and selectivity toward a single, desired target while minimizing off-target interactions. This review studies the evolution of the privileged structure concept, highlighting examples and their impact, and details the strategic application of these scaffolds in fragment-based and structure-based design, showing their enduring utility in developing novel therapeutics