DrugHIVE: Target-specific spatial drug design and optimization with a hierarchical generative model

ABSTRACT Rapid advancement in the computational methods of structure-based drug design has led to their widespread adoption as key tools in the early drug development process. Recently, the remarkable growth of available crystal structure data and libraries of commercially available or readily synthesizable molecules have unlocked previously inaccessible regions of chemical space for drug development. Paired with improvements in virtual ligand screening methods, these expanded libraries are having a significant impact on the success of early drug design efforts. However, screening-based methods are limited in their scalability due to computational limits and the sheer scale of drug-like space. An approach within the quickly evolving field of artificial intelligence (AI), deep generative modeling, is extending the reach of molecular design beyond classical methods by learning the fundamental intra- and inter-molecular relationships in drug-target systems from existing data. In this work we introduce DrugHIVE, a deep hierarchical structure-based generative model that enables fine-grained control over molecular generation. Our model outperforms state of the art autoregressive and diffusion-based methods on common benchmarks and in speed of generation. Here, we demonstrate DrugHIVE’s capacity to accelerate a wide range of common drug design tasks such as de novo generation, molecular optimization, scaffold hopping, linker design, and high throughput pattern replacement. Our method is highly scalable and can be applied to high confidence AlphaFold predicted receptors, extending our ability to generate high quality drug-like molecules to a majority of the unsolved human proteome.