Beyond Small Molecules: Applying Fragment Molecular Orbital Sygnature Platform (FMO-SP) to Emerging Modalities

Drug discovery is rapidly expanding beyond traditional small molecules to encompass new therapeutic modalities capable of addressing previously "undruggable" targets. Between 2015 and mid-2025, FDA approvals increasingly included biologics and emerging therapeutic modalities such as antibody-drug conjugates (ADCs), nucleic acid therapeutics, and other nontraditional approaches. In parallel, PROTACs and molecular glue degraders (MGDs) have expanded rapidly in clinical development. These innovations are reshaping therapeutic strategies in oncology, metabolic disease, and rare disorders, but they introduce major design challenges: large and shallow protein-protein interfaces, competition with extensive native interaction networks, ternary complex cooperativity, and the intricacies of nucleic-acid recognition. Addressing these problems requires accurate quantum-mechanical methods capable of resolving the underlying molecular interactions. The Fragment Molecular Orbital Sygnature Platform (FMO-SP) integrates quantum mechanics with automated workflows and intuitive visual analytics to provide residue-level, quantified energetic insights. These capabilities enable rational optimization of ADCs, PROTAC, and MGD ternary complexes, GPCR-peptide, PPi interfaces, and RNA/DNA modulators. Building on Chap. 4 (small molecules), this chapter demonstrates how FMO-SP elucidates mechanisms of action and guides design across emerging therapeutic modalities, supporting more predictive and resource-efficient drug discovery.