Simon Olsson

Tony Shen, Seonghwan Seo, Ross Irwin et al.

Many generative applications, such as synthesis-based 3D molecular design, involve constructing compositional objects with continuous features. Here, we introduce Compositional Generative Flows (CGFlow), a novel framework that extends flow matching to generate objects in compositional steps while modeling continuous states. Our key insight is that modeling compositional state transitions can be formulated as a straightforward extension of the flow matching interpolation process. We further build upon the theoretical foundations of generative flow networks (GFlowNets), enabling reward-guided sampling of compositional structures. We apply CGFlow to synthesizable drug design by jointly designing the molecule's synthetic pathway with its 3D binding pose. Our approach achieves state-of-the-art binding affinity on all 15 targets from the LIT-PCBA benchmark, and 5.8$\times$ improvement in sampling efficiency compared to 2D synthesis-based baseline. To our best knowledge, our method is also the first to achieve state of-art-performance in both Vina Dock (-9.38) and AiZynth success rate (62.2\%) on the CrossDocked benchmark.

Ross Irwin, Alessandro Tibo, Jon Paul Janet et al.

Methods for jointly generating molecular graphs along with their 3D conformations have gained prominence recently due to their potential impact on structure-based drug design. Current approaches, however, often suffer from very slow sampling times or generate molecules with poor chemical validity. Addressing these limitations, we propose Semla, a scalable E(3)-equivariant message passing architecture. We further introduce an unconditional 3D molecular generation model, SemlaFlow, which is trained using equivariant flow matching to generate a joint distribution over atom types, coordinates, bond types and formal charges. Our model produces state-of-the-art results on benchmark datasets with as few as 20 sampling steps, corresponding to a two order-of-magnitude speedup compared to state-of-the-art. Furthermore, we highlight limitations of current evaluation methods for 3D generation and propose new benchmark metrics for unconditional molecular generators. Finally, using these new metrics, we compare our model's ability to generate high quality samples against current approaches and further demonstrate SemlaFlow's strong performance.