BEGAN: Boltzmann-Reweighted Data Augmentation for Enhanced GAN-Based Molecule Design in Insect Pheromone Receptors

Abstract

Identifying molecules that bind strongly to target proteins in rational drug design is crucial. Machine learning techniques, such as generative adversarial networks (GAN), are now essential tools for generating such molecules. In this study, we present an enhanced method for molecule generation using objective-reinforced GANs. Specifically, we introduce BEGAN (Boltzmann-Enhanced GAN), a novel approach that adjusts molecule occurrence frequencies during training based on the Boltzmann distribution exp(−∆U/τ), where ∆U represents the estimated binding free energy derived from docking algorithms and τ is a temperature-related scaling hyperparameter. This Boltzmann reweighting process shifts the generation process towards molecules with higher binding affinities, allowing the GAN to explore molecular spaces with superior binding properties. The reweighting process can also be refined through multiple iterations without altering the overall distribution shape. To validate our approach, we apply it to the design of sex pheromone analogs targeting Spodoptera frugiperda pheromone receptor SfruOR16, illustrating that the Boltzmann reweighting significantly increases the likelihood of generating promising sex pheromone analogs with improved binding affinities to SfruOR16, further supported by atomistic molecular dynamics simulations. Furthermore, we conduct a comprehensive investigation into parameter dependencies and propose a reasonable range for the hyperparameter τ. Our method offers a promising approach for optimizing molecular generation for enhanced protein binding, potentially increasing the efficiency of drug discovery pipelines.