AI for targeted polypharmacology: The next frontier in drug discovery

In drug discovery, targeted polypharmacology, i.e., targeting multiple molecular targets with a single drug, is redefining therapeutic design to address complex diseases. Pre-selected pharmacological profiles, as exemplified in kinase drugs, promise enhanced efficacy and reduced toxicity. Historically, many of such drugs were discovered serendipitously, limiting predictability and efficacy, but currently artificial intelligence (AI) offers a transformative solution. Machine learning and deep learning techniques enable modeling protein structures, generating novel compounds, and decoding their polypharmacological effects, opening an avenue for more systematic and predictive multi-target drug design. This review explores the use of AI in identifying synergistic co-targets and delineating them from anti-targets that lead to adverse effects, and then discusses advances in AI-enabled docking, generative chemistry, and proteochemometric modeling of proteomewide compound interactions, in the context of polypharmacology. We also provide insights into challenges ahead.