The Department of Health and Human Services, specifically the National Institutes of Health, is seeking proposals for the topic of "Harnessing Artificial Intelligence and Polypharmacology to Discover Pharmacotherapeutics for Substance Use Disorders (R43/R44 Clinical Trials Not Allowed)". This solicitation aims to leverage AI/ML tools to identify pharmacotherapeutic development candidates with lower toxicity and higher efficacy for the prevention or treatment of substance use disorders (SUDs). The traditional drug discovery paradigm of single-target-based approaches has limitations in addressing the complex mechanisms and polysubstance use associated with SUDs. Polypharmacology, the study of how drug molecules interact with multiple targets, is emerging as a new paradigm for drug development in multifactorial diseases like SUDs. The use of AI/ML technologies trained in polypharmacology can enhance the discovery and development efforts by identifying the best targets, designing effective multi-target directed ligands (MTDLs), and predicting the effects of binding to multiple biological targets. The research objectives include identifying and validating disease targets, screening potential compounds, developing assays, synthesizing novel compounds, and conducting in vitro and in vivo studies. The Small Business Innovation Research (SBIR) program offers Phase I and Phase II funding opportunities to support the technical merit, feasibility, and commercial potential of the proposed research. Successful SBIR projects are expected to attract strategic partners or investors for ultimate commercialization.