Abstract
In this work, we introduce auxiliary discriminator sequence generative adversarial networks (ADSeqGAN), a novel approach for molecular generation in small-sample data sets. Traditional generative models often struggle with limited training data, particularly in drug discovery, where molecular data sets for specific therapeutic targets, such as nucleic acid binders and central nervous system (CNS) drugs, are scarce. ADSeqGAN addresses this challenge by integrating an auxiliary random forest classifier as an additional discriminator into the GAN framework, significantly improving molecular generation quality and class specificity. Our method incorporates a pretrained generator and Wasserstein distance to enhance training stability and diversity. We evaluated ADSeqGAN across three representative cases. First, on nucleic acid- and protein-targeting molecules, ADSeqGAN shows superior capability in generating nucleic acid binders compared with baseline models. Second, through oversampling, it markedly improves CNS drug generation, achieving higher yields than traditional de novo models. Third, in cannabinoid receptor type 1 (CB1) ligand design, ADSeqGAN generates novel druglike molecules with 32.8% predicted actives surpassing hit rates of CB1-focused and general-purpose libraries when assessed by a target-specific LRIP-SF scoring function. Overall, ADSeqGAN offers a versatile framework for molecular design in data-scarce scenarios with demonstrated applications in nucleic acid binders, CNS drugs, and CB1 ligands.