Work done during an internship at NVIDIA.

Work done during an internship at NVIDIA.

We introduce InVirtuoGen, a discrete flow generative model for fragmented SMILES for de novo and fragment-constrained generation, and target-property/lead optimization of small molecules. The model learns to transform a uniform source over all possible tokens into the data distribution. Unlike masked models, its training loss accounts for predictions on all sequence positions at every denoising step, shifting the generation paradigm from completion to refinement, and decoupling the number of sampling steps from the sequence length. For \textit{de novo} generation, InVirtuoGen achieves a stronger quality-diversity pareto frontier than prior fragment-based models and competitive performance on fragment-constrained tasks. For property and lead optimization, we propose a hybrid scheme that combines a genetic algorithm with a Proximal Property Optimization fine-tuning strategy adapted to discrete flows. Our approach sets a new state-of-the-art on the Practical Molecular Optimization benchmark, measured by top-10 AUC across tasks, and yields higher docking scores in lead optimization than previous baselines. InVirtuoGen thus establishes a versatile generative foundation for drug discovery, from early hit finding to multi-objective lead optimization. We further contribute to open science by releasing pretrained checkpoints and code, making our results fully reproducible\footnote{https://github.com/invirtuolabs/InVirtuoGen_results}.

Table 4: We report the mean and standard deviation of AUC Top-10 from 5 independent runs. Figure 9. Though SA_Score is not a great metric, we could see that synthesis-based methods have The diversity is defined as the averaged internal distance within a batch of molecules, measured by Tanimoto similarity. We could see a general trend that the stronger a model is in optimization, the less diverse the results are. In this section, we elaborate the implementation details for each method. To avoid the bias introduced by different dataset, e.g., ZINC, ChemBL, for all the methods, we use ZINC to (i) train/pretrain the model; (ii) provide initial molecule set and (iii) extract vocabulary set.

Large language models (LLMs) have large potential for molecular optimization, as they can gather external chemistry tools and enable collaborative interactions to iteratively refine molecular candidates. However, this potential remains underexplored, particularly in the context of structured reasoning, interpretability, and comprehensive tool-grounded molecular optimization. To address this gap, we introduce MT-Mol, a multi-agent framework for molecular optimization that leverages tool-guided reasoning and role-specialized LLM agents. Our system incorporates comprehensive RDKit tools, categorized into five distinct domains: structural descriptors, electronic and topological features, fragment-based functional groups, molecular representations, and miscellaneous chemical properties. Each category is managed by an expert analyst agent, responsible for extracting task-relevant tools and enabling interpretable, chemically grounded feedback. MT-Mol produces molecules with tool-aligned and stepwise reasoning through the interaction between the analyst agents, a molecule-generating scientist, a reasoning-output verifier, and a reviewer agent. As a result, we show that our framework shows the state-of-the-art performance of the PMO-1K benchmark on 17 out of 23 tasks.

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.

Fragment-based drug discovery, in which molecular fragments are assembled into new molecules with desirable biochemical properties, has achieved great success. However, many fragment-based molecule generation methods show limited exploration beyond the existing fragments in the database as they only reassemble or slightly modify the given ones. To tackle this problem, we propose a new fragment-based molecule generation framework with retrieval augmentation, namely Fragment Retrieval-Augmented Generation (f-RAG). f-RAG is based on a pre-trained molecular generative model that proposes additional fragments from input fragments to complete and generate a new molecule. Given a fragment vocabulary, f-RAG retrieves two types of fragments: (1) hard fragments, which serve as building blocks that will be explicitly included in the newly generated molecule, and (2) soft fragments, which serve as reference to guide the generation of new fragments through a trainable fragment injection module. To extrapolate beyond the existing fragments, f-RAG updates the fragment vocabulary with generated fragments via an iterative refinement process which is further enhanced with post-hoc genetic fragment modification. f-RAG can achieve an improved exploration-exploitation trade-off by maintaining a pool of fragments and expanding it with novel and high-quality fragments through a strong generative prior.

The proposed method shows a stateof-the-art score of 16.213, significantly outperforming the reported best score in the benchmark genetic algorithms (e.g., Jensen, 2019). of 15.185, in practical molecular optimization The recent work of Gao et al. (2022a) proposes a practical (PMO), which is an official benchmark for molecular optimization (PMO) benchmark, emphasizing sample-efficient molecular optimization. Remarkably, the importance of sample efficiency in de novo molecular ours exceeds all baselines, including reinforcement optimization for practical applicability. The benchmark is learning, Bayesian optimization, generative reasonable because real-world applications of molecule optimization models, GFlowNets, and genetic algorithms, (e.g., drug discovery) require expensive scoring in 14 out of 23 tasks. Our code is available at processes such as wet lab experiments.