Cracking the Sulfur Code: Garlic Bioactive Molecules as Multi-Target Blueprints for Drug Discovery

Garlic (Allium sativum L.) has served as a food source and medicinal agent for over thousands of years. Bioactive constituents, including allicin, diallyl sulfide/disulfide/trisulfide, ajoene, and S-allyl-cysteine, demonstrate antioxidant, anti-inflammatory, antithrombotic, antineoplastic, antimicrobial and neuroprotective properties. Convergent mechanistic evidence suggests the modulation of redox homeostasis, attenuation of pro-inflammatory signaling, regulation of platelet activation, and induction of apoptosis and cell-cycle arrest in tumor models. Computational studies, in conjunction with wet-lab data, offer molecular-level insights and guide candidate prioritization. Density functional theory elucidates radical-scavenging pathways and electronic descriptors that account for redox activity. Structure-based methods, including docking, molecular dynamics, and MM-GBSA, elucidate potential interactions between organosulfur scaffolds and enzymes or receptors pertinent to pharmacological effects. In silico ADME/Tox platforms predict generally favorable oral absorption for hydrophobic allyl sulfides, while polar derivatives exhibit more limited brain penetration. Emerging AI/ML pipelines combine network pharmacology with QSAR to focus on important targets and chemical types, while also spotting potential development. Formulation strategies, including nanoencapsulation and controlled-release systems, are utilized to stabilize labile thiosulfinates and modulate hydrogen-sulfide-releasing profiles, with potential applications in various disease conditions. Significant challenges encompass the standardization of preparations, variability in pharmacokinetics, heterogeneity in dose–response relationships, and interactions between drugs and nutrients or other drugs. The integration of mechanistic, computational, and formulation insights delineates a systematic approach to progress garlic-derived agents from diverse natural products to reproducible, mechanism-guided pharmaceuticals.