Auxiliary Discrminator Sequence Generative Adversarial Networks (ADSeqGAN) for Few Sample Molecule Generation

TL;DR

ADSeqGAN is a novel GAN-based framework that enhances molecular generation from small datasets by integrating an auxiliary classifier, pretrained components, and Wasserstein distance, leading to improved quality and diversity in drug discovery applications.

Contribution

This work introduces ADSeqGAN, the first GAN model with an auxiliary classifier and pretrained components specifically designed for small-sample molecular generation.

Findings

Outperforms baseline models in nucleic acid binder generation

Significantly improves CNS drug oversampling results

Generates novel CB1 ligands with high predicted activity

Abstract

In this work, we introduce Auxiliary Discriminator Sequence Generative Adversarial Networks (ADSeqGAN), a novel approach for molecular generation in small-sample datasets. Traditional generative models often struggle with limited training data, particularly in drug discovery, where molecular datasets for specific therapeutic targets, such as nucleic acids 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 improves molecular generation quality and class specificity. Our method incorporates pretrained generator and Wasserstein distance to enhance training stability and diversity. We evaluate ADSeqGAN across three representative cases. First, on nucleic acid- and protein-targeting molecules, ADSeqGAN shows superior capability in generating nucleic acid binders compared to 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.