Background: Chemical structure is a vital consideration early in the drug development process. Its role in analysis of safety and efficacy is relatively diminished after drugs are approved for clinical use. This interdisciplinary study explores a strategy by which readily available clinical data may be used along with structural features of drugs to identify associations with potential utility for both clinical decision-making and drug development. Methods: Chemical functional groups and structural groups (SGs) of 261 drugs were manually classified in tiers, and their incidence of gastrointestinal (GI) and central nervous system (CNS) adverse drug reactions (ADRs) were obtained from a clinical database. Drugs with an GI or CNS ADR incidence of at least 10% were analyzed for correlations with their functional and SGs. Results: Eight statistically significant associations were detected by preliminary analysis: piperazine and methylene groups were associated with higher rate of CNS ADRs; while amides, secondary alcohols, and di-substituted phenyl groups were associated with lower rates of GI or CNS ADRs or both. Conclusions: Although further study is necessary to understand these associations and build upon this strategy, this exploratory analysis establishes a methodology by which chemical properties of drugs may be used to aid in clinical decision-making when choosing between otherwise equivalent drug therapy options, as the presence of specific groups on drugs may be associated with increased or decreased risks of specific ADRs.