Multi-Target and Synergistic Therapeutic Strategies in Modern Drug Discovery

Dear Colleagues,

The growing recognition that most human diseases are multifactorial and network-based has challenged the traditional “one drug–one target” paradigm. Conditions such as metabolic and cardiovascular disorders, cancer, neurodegenerative diseases, and chronic inflammation arise from the dysregulation of multiple interconnected molecular pathways. Consequently, multi-target and synergistic therapeutic strategies have emerged as powerful alternatives for improving efficacy, overcoming resistance, and minimizing adverse effects.

This Special Issue will highlight advances in polypharmacology, drug repurposing, and combination therapy, including the development of dual- and multi-mechanistic compounds, rationally designed drug combinations, and multi-component formulations from both synthetic and natural sources. We particularly welcome studies integrating computational and network pharmacology, molecular modeling, chemoinformatics, and AI-assisted screening with in vitro, in vivo, and ex vivo pharmacological investigations. Contributions exploring omics-based profiling, nanotechnology-driven delivery systems, and research on nutraceuticals, phytocomplexes, and bioactive mixtures with complementary biological actions are also encouraged. Importantly, we invite studies that bridge preclinical discoveries with translational and clinical research, including early-phase or proof-of-concept clinical trials evaluating the safety, efficacy, and mechanistic rationale of synergistic or multi-target strategies. By integrating chemical, biological, computational, and clinical perspectives, this Special Issue will promote a multidisciplinary understanding of how synergistic and multi-target paradigms derived from natural combinations to rationally engineered therapeutics can advance innovation in modern drug discovery and precision medicine.

Dr. Vincenzo Piccolo
Guest Editor

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