RESUMEN
Designing drugs capable of binding to the structure of target proteins for treating diseases is essential in drug development. Recent remarkable advancements in geometric deep learning have led to unprecedented progress in three-dimensional (3D) generation of ligands that can bind to the protein pocket. However, most existing methods primarily focus on modeling the geometric information of ligands in 3D space. Consequently, these methods fail to consider that the binding of proteins and ligands is a phenomenon driven by intrinsic physicochemical principles. Motivated by this understanding, we propose PIDiff, a model for generating molecules by accounting in the physicochemical principles of protein-ligand binding. Our model learns not only the structural information of proteins and ligands but also to minimize the binding free energy between them. To evaluate the proposed model, we introduce an experimental framework that surpasses traditional assessment methods by encompassing various essential aspects for the practical application of generative models to actual drug development. The results confirm that our model outperforms baseline models on the CrossDocked2020 benchmark dataset, demonstrating its superiority. Through diverse experiments, we have illustrated the promising potential of the proposed model in practical drug development.
RESUMEN
The composition and diversity of gut microbiota significantly influence the immune system and are linked to various diseases, including inflammatory and allergy disorders. While considerable research has focused on exploring single bacterial species or consortia, the optimal strategies for microbiota-based therapeutics remain underexplored. Specifically, the comparative effectiveness of bacterial consortia versus individual species warrants further investigation. In our study, we assessed the impact of the bacterial consortium MPRO, comprising Lactiplantibacillus plantarum HY7712, Bifidobacterium animalis ssp. lactis HY8002, and Lacticaseibacillus casei HY2782, in comparison to its individual components. The administration of MPRO demonstrated enhanced therapeutic efficacy in experimental models of atopic dermatitis and inflammatory colitis when compared to single strains. MPRO exhibited the ability to dampen inflammatory responses and alter the gut microbial landscape significantly. Notably, MPRO administration led to an increase in intestinal CD103+CD11b+ dendritic cells, promoting the induction of regulatory T cells and the robust suppression of inflammation in experimental disease settings. Our findings advocate the preference for bacterial consortia over single strains in the treatment of inflammatory disorders, carrying potential clinical relevance.