Validating Fractalkine receptor as a target and identifying candidates for drug discovery against type 2 diabetes.

Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases employing abnormal levels of insulin. Enhancing the insulin production is greatly aided by the regulatory mechanisms of the Fractalkine receptor (CX3CR1) system in islet ß-cell function. However, elements including a high-fat diet, obesity, and ageing negatively impact the expression of CX3CR1 in islets. CX3CL1/CX3CR1 receptor-ligand complex is now recognized as a novel therapeutic target. It suggests that T2DM-related ß-cell dysfunction may result from lower amount of these proteins. We analyzed the differential expression of CX3CR1 gene samples taken from persons with T2DM using data obtained from the Gene Expression Omnibus database. Homology modeling enabled us to generate the three-dimensional structure of CX3CR1 and a possible binding pocket. The optimized CX3CR1 structure was subjected to rigorous screening against a massive library of 693 million drug-like molecules from the ZINC15 database. This screening process led to the identification of three compounds with strong binding affinity at the identified binding pocket of CX3CR1. To further evaluate the potential of these compounds, molecular dynamics simulations were conducted over a 50 ns time scale to assess the stability of the protein-ligand complexes. These simulations revealed that ZINC000032506419 emerged as the most promising drug-like compound among the three potent molecules. The discovery of ZINC000032506419 holds exciting promise as a potential therapeutic agent for T2D and other related metabolic disorders. These findings pave the way for the development of effective medications to address the complexities of T2DM and its associated metabolic diseases.

Potential molecular metabolic mechanisms underlying the effects of cimifugin in gastric cancer through single-cell and bulk RNA sequencing combined with network pharmacology.

Background: Gastric cancer (GC) is a leading cause of cancer-related mortality worldwide, posing a significant clinical challenge due to its complex tumor microenvironment (TME) and metabolic heterogeneity. Despite continuous improvements in treatment strategies including surgery, chemotherapy, and targeted therapies, the metabolic reprogramming in GC continues to impede treatment efficacy, highlighting an urgent need for the development of novel therapeutic strategies. This persistent issue underscores the urgent need for novel therapeutic approaches that can effectively address the diverse and dynamic characteristics of GC. Cimifugin, a traditional Chinese medicine (TCM), has garnered attention for its potential role in alleviating inflammation, neurological disorders, pain, and metabolic disorders. Its multi-targeting properties and minimal side effects suggest a broad potential for cancer management, which is currently being explored. This study aims to delineate the molecular mechanisms that cimifugin may impact within the TME and metabolic pathways of GC, with the expectation of contributing to a deeper understanding of GC and the development of innovative treatment strategies. Methods: We identified the GC-related TME cell types and metabolic profiles and pathways by using relevant data from the single-cell RNA sequencing (scRNA-seq) database GSE134520 and the stomach adenocarcinoma (STAD) data set from The Cancer Genome Atlas (TCGA). We also assessed the effects of cimifugin on MKN28 cell proliferation, invasion, and migration. By using six public platforms, we comprehensively predicted the potential biological targets of cimifugin. Clinical prognosis and immunohistochemistry (IHC), molecular docking, and dynamics simulations were used to confirm the clinical relevance and stability of the aforementioned targets. Results: Cimifugin inhibited MKN28 cell proliferation, migration, and invasion. Cimifugin may potentially act on various metabolic pathways in GC, including folate biosynthesis, xenobiotic metabolism via cytochrome P450 (CYP), glutathione metabolism, steroid hormone biosynthesis, and tryptophan metabolism. Cimifugin was noted to stably bind to three significant core targets associated with metabolic reprogramming in GC: AKR1C2, MAOB, and PDE2A; all three targets were strongly expressed in endocrince cells, pit mucous cells (PMCs), and common myeloid progenitors (CMPs). Conclusions: We verified the pharmacological effects of cimifugin on GC cell proliferation, invasion, and migration. AKR1C2, MAOB, and PDE2A were identified as the key targets of cimifugin in GC-related metabolic reprogramming and pathogenesis. Our research provides preliminary insights into the potential therapeutic effects of cimifugin, which could be considered for future exploration in the context of GC treatment.

MDSPACE: Extracting Continuous Conformational Landscapes from Cryo-EM Single Particle Datasets Using 3D-to-2D Flexible Fitting based on Molecular Dynamics Simulation.

This article presents an original approach for extracting atomic-resolution landscapes of continuous conformational variability of biomolecular complexes from cryo electron microscopy (cryo-EM) single particle images. This approach is based on a new 3D-to-2D flexible fitting method, which uses molecular dynamics (MD) simulation and is embedded in an iterative conformational-landscape refinement scheme. This new approach is referred to as MDSPACE, which stands for Molecular Dynamics simulation for Single Particle Analysis of Continuous Conformational hEterogeneity. The article describes the MDSPACE approach and shows its performance using synthetic and experimental datasets.