Molecular evolution is the process of simulating the natural evolution of molecules in chemical space to explore potential molecular structures and properties. The relationships between similar molecules are often described through transformations such as adding, deleting, and modifying atoms and chemical bonds, reflecting specific evolutionary paths. Existing molecular representation methods mainly focus on mining data, such as atomic-level structures and chemical bonds directly from the molecules, often overlooking their evolutionary history. Consequently, we aim to explore the possibility of enhancing molecular representations by simulating the evolutionary process. We extract and analyze the changes in the evolutionary pathway and explore combining it with existing molecular representations. Therefore, this paper proposes the molecular evolutionary network (MEvoN) for molecular representations. First, we construct the MEvoN using molecules with a small number of atoms and generate evolutionary paths utilizing similarity calculations. Then, by modeling the atomic-level changes, MEvoN reveals their impact on molecular properties. Experimental results show that the MEvoN-based molecular property prediction method significantly improves the performance of traditional end-to-end algorithms by approximately 33% on both the QM7 and QM9 datasets.

The prediction of compound–protein interactions (CPIs) is crucial for drug discovery. Most existing CPI prediction models rely on protein sequence information as input. However, in early-stage drug development, particularly in phenotype-driven studies or compound-response analyses, proteins are often annotated only with functional labels, and their sequences remain undetermined. Consequently, current methods are inapplicable in such scenarios. Furthermore, our experiments find that even when large-scale perturbations were applied to protein sequences, the predictive performance of the existing models did not show a significant decline. It indicates that the high investment in sequencing may not bring corresponding returns. To address the above issues, we propose an inexpensive, protein-sequencing-free framework BioText-CPI, based on the Biomedical Textual description of protein for CPI prediction. Firstly, during the pre-training stage of the model, we use contrastive learning to align protein texts and sequence modalities. Subsequently, we add biological text descriptions of proteins to the existing public CPI dataset to construct a new CPI dataset. Finally, in the CPI prediction stage, the sequence and biomedical text descriptions of proteins can be used as the input for CPI prediction either separately or simultaneously to meet the application requirements of different scenarios. The experiments demonstrate that BioText-CPI achieves comparable effects to the traditional methods when only the biomedical description of protein is input. Moreover, when the two modalities of protein information are input simultaneously, BioText-CPI achieves state-of-the-art performance across multiple scenarios.

Generating graph-structured molecular data involves understanding complex graph distributions. This is crucial for de novo drug molecule design, especially when incorporating drug-drug interactions (DDIs). Existing graph generative methods often struggle to capture the graphs' permutation invariance or fail to model the collaborative dependencies among various molecular components, including atom-, bond-, and textual-level DDI information. To address these limitations, we propose DDI-Diff, a knowledge-driven dual diffusion model for DDI-based drug design. DDI-Diff employs a continuous time framework and introduces a collaborative graph diffusion process, leveraging a stochastic differential equations (SDEs) system to jointly model node and edge distribution. During pretraining, we use a large-scale, unconditional dataset, followed by conditional training on DrugBank. This enhances the model's ability to generate molecular structures that align with DDI-aware knowledge, effectively capturing the collaborative effects among drugs. Then, we validated our model using DrugBank, demonstrating that DDI-Diff improves accuracy by 4.35% more than current state-of-the-art methods across all labels and highlighting its potential in collaborative drug design.

Due to their excellent drug-like and pharmacokinetic properties, small molecule drugs are widely used to treat various diseases, making them a critical component of drug discovery. In recent years, with the rapid development of deep learning (DL) techniques, DL-based small molecule drug discovery methods have achieved excellent performance in prediction accuracy, speed, and complex molecular relationship modeling compared to traditional machine learning approaches. These advancements enhance drug screening efficiency, streamline optimization, and provide more precise and effective solutions for drug discovery. Contributing to this field's development, this paper aims to systematically summarize and generalize the recent key tasks and representative techniques in graph-structured small molecule drug discovery. Specifically, we provide an overview of the major tasks in small-molecule drug discovery and their interrelationships. Next, we analyze the six core tasks, summarizing the related methods, commonly used datasets, and technological development trends. Finally, we discuss key challenges, such as interpretability and out-of-distribution generalization, and offer our insights into future research directions for small molecule drug discovery.