A Deep Generative Model for the Design of Synthesizable Ionizable Lipids

Lipid nanoparticles (LNPs) are vital in modern biomedicine, enabling the effective delivery of mRNA for vaccines and therapies by protecting it from rapid degradation. Among the components of LNPs, ionizable lipids play a key role in RNA protection and facilitate its delivery into the cytoplasm. However, designing ionizable lipids is complex. Deep generative models can accelerate this process and explore a larger candidate space compared to traditional methods. Due to the structural differences between lipids and small molecules, existing generative models used for small molecule generation are unsuitable for lipid generation. To address this, we developed a deep generative model specifically tailored for the discovery of ionizable lipids. Our model generates novel ionizable lipid structures and provides synthesis paths using synthetically accessible building blocks, addressing synthesizability. This advancement holds promise for streamlining the development of lipid-based delivery systems, potentially accelerating the deployment of new therapeutic agents, including mRNA vaccines and gene therapies.

Generative Model for Synthesizing Ionizable Lipids: A Monte Carlo Tree Search Approach

Ionizable lipids are essential in developing lipid nanoparticles (LNPs) for effective messenger RNA (mRNA) delivery. While traditional methods for designing new ionizable lipids are typically time-consuming, deep generative models have emerged as a powerful solution, significantly accelerating the molecular discovery process. However, a practical challenge arises as the molecular structures generated can often be difficult or infeasible to synthesize. This project explores Monte Carlo tree search (MCTS)-based generative models for synthesizable ionizable lipids. Leveraging a synthetically accessible lipid building block dataset and two specialized predictors to guide the search through chemical space, we introduce a policy network guided MCTS generative model capable of producing new ionizable lipids with available synthesis pathways.