Daily Papers

Traditional molecular string representations, such as SMILES, often pose challenges for AI-driven molecular design due to their non-sequential depiction of molecular substructures. To address this issue, we introduce Sequential Attachment-based Fragment Embedding (SAFE), a novel line notation for chemical structures. SAFE reimagines SMILES strings as an unordered sequence of interconnected fragment blocks while maintaining full compatibility with existing SMILES parsers. It streamlines complex generative tasks, including scaffold decoration, fragment linking, polymer generation, and scaffold hopping, while facilitating autoregressive generation for fragment-constrained design, thereby eliminating the need for intricate decoding or graph-based models. We demonstrate the effectiveness of SAFE by training an 87-million-parameter GPT2-like model on a dataset containing 1.1 billion SAFE representations. Through extensive experimentation, we show that our SAFE-GPT model exhibits versatile and robust optimization performance. SAFE opens up new avenues for the rapid exploration of chemical space under various constraints, promising breakthroughs in AI-driven molecular design.

Fragment-based drug discovery has been an effective paradigm in early-stage drug development. An open challenge in this area is designing linkers between disconnected molecular fragments of interest to obtain chemically-relevant candidate drug molecules. In this work, we propose DiffLinker, an E(3)-equivariant 3D-conditional diffusion model for molecular linker design. Given a set of disconnected fragments, our model places missing atoms in between and designs a molecule incorporating all the initial fragments. Unlike previous approaches that are only able to connect pairs of molecular fragments, our method can link an arbitrary number of fragments. Additionally, the model automatically determines the number of atoms in the linker and its attachment points to the input fragments. We demonstrate that DiffLinker outperforms other methods on the standard datasets generating more diverse and synthetically-accessible molecules. Besides, we experimentally test our method in real-world applications, showing that it can successfully generate valid linkers conditioned on target protein pockets.

Drug discovery is a complex process that involves multiple scenarios and stages, such as fragment-constrained molecule generation, hit generation and lead optimization. However, existing molecular generative models can only tackle one or two of these scenarios and lack the flexibility to address various aspects of the drug discovery pipeline. In this paper, we present Generalist Molecular generative model (GenMol), a versatile framework that addresses these limitations by applying discrete diffusion to the Sequential Attachment-based Fragment Embedding (SAFE) molecular representation. GenMol generates SAFE sequences through non-autoregressive bidirectional parallel decoding, thereby allowing utilization of a molecular context that does not rely on the specific token ordering and enhanced computational efficiency. Moreover, under the discrete diffusion framework, we introduce fragment remasking, a strategy that optimizes molecules by replacing fragments with masked tokens and regenerating them, enabling effective exploration of chemical space. GenMol significantly outperforms the previous GPT-based model trained on SAFE representations in de novo generation and fragment-constrained generation, and achieves state-of-the-art performance in goal-directed hit generation and lead optimization. These experimental results demonstrate that GenMol can tackle a wide range of drug discovery tasks, providing a unified and versatile approach for molecular design.

We present MeshSegmenter, a simple yet effective framework designed for zero-shot 3D semantic segmentation. This model successfully extends the powerful capabilities of 2D segmentation models to 3D meshes, delivering accurate 3D segmentation across diverse meshes and segment descriptions. Specifically, our model leverages the Segment Anything Model (SAM) model to segment the target regions from images rendered from the 3D shape. In light of the importance of the texture for segmentation, we also leverage the pretrained stable diffusion model to generate images with textures from 3D shape, and leverage SAM to segment the target regions from images with textures. Textures supplement the shape for segmentation and facilitate accurate 3D segmentation even in geometrically non-prominent areas, such as segmenting a car door within a car mesh. To achieve the 3D segments, we render 2D images from different views and conduct segmentation for both textured and untextured images. Lastly, we develop a multi-view revoting scheme that integrates 2D segmentation results and confidence scores from various views onto the 3D mesh, ensuring the 3D consistency of segmentation results and eliminating inaccuracies from specific perspectives. Through these innovations, MeshSegmenter offers stable and reliable 3D segmentation results both quantitatively and qualitatively, highlighting its potential as a transformative tool in the field of 3D zero-shot segmentation. The code is available at https://github.com/zimingzhong/MeshSegmenter.