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

Garlic (<i>Allium sativum</i> 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 <i>S</i>-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. <i>In silico</i> 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.