Quantitative structure-activity relationship (QSAR) models were developed for dihydrofolate reductase (DHFR) inhibition by pyrimethamine derivatives using small molecule descriptors derived from MOE and/or QikProp and linear or nonlinear modeling. During this analysis, the best QSAR models were identified when using MOE descriptors and nonlinear models (artificial neural networks) optimized by evolutionary computation. The resulting models can be used to identify key descriptors for DHFR inhibition and are useful for high-throughput screening of novel drug leads.