AI-based prediction of protein-ligand binding affinity and discovery of potential natural product inhibitors against ERK2.

Determination of protein-ligand binding affinity (PLA) is a key technological tool in hit discovery and lead optimization, which is critical to the drug development process. PLA can be determined directly by experimental methods, but it is time-consuming and costly. In recent years, deep learning has been widely applied to PLA prediction, the key of which lies in the comprehensive and accurate representation of proteins and ligands. In this study, we proposed a multi-modal deep learning model based on the early fusion strategy, called DeepLIP, to improve PLA prediction by integrating multi-level information, and further used it for virtual screening of extracellular signal-regulated protein kinase 2 (ERK2), an ideal target for cancer treatment. Experimental results from model evaluation showed that DeepLIP achieved superior performance compared to state-of-the-art methods on the widely used benchmark dataset. In addition, by combining previously developed machine learning models and molecular dynamics simulation, we screened three novel hits from a drug-like natural product library. These compounds not only had favorable physicochemical properties, but also bound stably to the target protein. We believe they have the potential to serve as starting molecules for the development of ERK2 inhibitors.

SKA3 is a prognostic biomarker and associated with immune infiltration in bladder cancer.

BACKGROUND: Spindle and kinetochore­associated complex subunit 3 (SKA3) has recently been considered a key regulator of carcinogenesis. However, the connection between SKA3 and immune cell infiltration remains unknown. METHODS: The current study investigated the expression mode, prognostic effect, and functional role of SKA3 in different tumors, particularly bladder cancer using numerous databases, comprising TIMER, GEPIA, HPA, UALCAN, PrognoScan, and Kaplan-Meier Plotter. Differentially expressed gene and enrichment analyses were implemented on SKA3 using R packages "edgR" and "clusterProfiler". Immunohistochemistry was further used to validate the expression of SKA3 gene in bladder cancer. Following that, the relevance of SKA3 expression to immune infiltration level in bladder cancer was evaluated using TIMER. RESULTS: Overall, the level of SKA3 expression in tumor tissue significantly increased than in normal tissue. In bladder cancer and other tumors, patients with high SKA3 expression levels had worse overall survival (OS) (p = 0.016), disease-specific survival (DSS) (p = 0.00004), and disease-free survival (DFS) (p = 0.032). Additionally, the major molecular functions for SKA3 included nuclear division, mitotic nuclear division, mitotic sister chromatid segregation, humoral immune response, and cell chemotaxis. Additionally, SKA3 expression was found to be positively associated with enhanced M2 macrophage and T helper (Th) 2 cell infiltration in bladder cancer. CONCLUSIONS: Our study implies that SKA3 contributes to M2 macrophage and Th2 cell polarization by acting as an oncogene in bladder cancer. SKA3 might be a novel biomarker for evaluating prognosis and immune infiltration in bladder cancer.

[Progress on the Relationship Between the Regulation of Gastrointestinal System Function by Acupuncture and Central Nuclei].

Acupuncture has a good curative effect in the treatment of gastrointestinal system diseases, such as functional dyspepsia, ulcerative colitis, and constipation. The central nuclei which are involved in the mechanism of acupuncture in regulating the gastrointestinal system have become a research hotspot in recent years. In the present paper, the authors summarized the effect of acupuncture and the central nervous system on gastrointestinal function regulation. It was found that the regulation of gastrointestinal function by acupuncture involved many brain regions such as the amygdala, paraventricular nucleus, locus coeruleus, raphe nucleus, and dorsal nucleus of the vagus nerve. Of these, the limbic brain region had the closest relation. However, the included studies were animal experiments, which involved less research on nuclear group interactions. The role of central nuclei in the regulation of gastrointestinal function by acupuncture is unclear. Thus, the introduction of more advanced brain imaging techniques to observe brain dysfunction of central nuclei and the relativity of acupuncture in regulating gastrointestinal function will be the focus in the future study, which will contribute to determining the effective mechanism of acupuncture and moxibustion.