Retrosynthesis, the process of breaking down a target molecule into simpler precursors through a series of valid reactions, stands at the core of organic chemistry and drug development. Although recent machine learning (ML) research has advanced single-step retrosynthetic modeling and subsequent route searches, these solutions remain restricted by the extensive combinatorial space of possible pathways. Concurrently, large language models (LLMs) have exhibited remarkable chemical knowledge, hinting at their potential to tackle complex decision-making tasks in chemistry. In this work, we explore whether LLMs can successfully navigate the highly constrained, multi-step retrosynthesis planning problem. We introduce an efficient scheme for encoding reaction pathways and present a new route-level search strategy, moving beyond the conventional step-by-step reactant prediction. Through comprehensive evaluations, we show that our LLM-augmented approach excels at retrosynthesis planning and extends naturally to the broader challenge of synthesizable molecular design.

Jerry Cheung, Yuchen Zhuang, Yinghao Li, Pranav Shetty, Wantian Zhao, Sanjeev Grampurohit, Rampi Ramprasad, Chao Zhang. Proceedings of the 2024 Conference of the North American Chapter of the Association for Computational Linguistics: Human Language Technologies (Volume 1: Long Papers). 2024.

Recent works have shown the promise of learning pre-trained models for 3D molecular representation. However, existing pre-training models focus predominantly on equilibrium data and largely overlook off-equilibrium conformations. It is challenging to extend these methods to off-equilibrium data because their training objective relies on assumptions of conformations being the local energy minima. We address this gap by proposing a force-centric pretraining model for 3D molecular conformations covering both equilibrium and off-equilibrium data. For off-equilibrium data, our model learns directly from their atomic forces. For equilibrium data, we introduce zero-force regularization and forced-based denoising techniques to approximate near-equilibrium forces. We obtain a unified pre-trained model for 3D molecular representation with over 15 million diverse conformations. Experiments show that, with our pre-training objective, we increase forces accuracy by around 3 times compared to the un-pre-trained Equivariant Transformer model. By incorporating regularizations on equilibrium data, we solved the problem of unstable MD simulations in vanilla Equivariant Transformers, achieving state-of-the-art simulation performance with 2.45 times faster inference time than NequIP. As a powerful molecular encoder, our pre-trained model achieves on-par performance with state-of-the-art property prediction tasks.

Learning 3D representations of point clouds that generalize well to arbitrary orientations is a challenge of practical importance in domains ranging from computer vision to molecular modeling. The proposed approach uses a concentric spherical spatial representation, formed by nesting spheres discretized the icosahedral grid, as the basis for structured learning over point clouds. We propose rotationally equivariant convolutions for learning over the concentric spherical grid, which are incorporated into a novel architecture for representation learning that is robust to general rotations in 3D. We demonstrate the effectiveness and extensibility of our approach to problems in different domains, such as 3D shape recognition and predicting fundamental properties of molecular systems.