Interaction of molecular mechanisms of plant-derived metabolites in Type 2 diabetes mellitus: A network pharmacology, docking and molecular dynamics approach on AKT1 kinase

Abstract

• The combining of molecular docking molecular dynamics and network pharmacology provides a way for the study of traditional medicine. • Based on the theory of Indian medicine system is the relatively explicit compatibility of active materials. • The reliability of the results of these two techniques deserves further experimental investigation. T2DM is a common metabolic disease with enormous effects on health worldwide; moreover, the use of phytochemicals as therapeutic compounds has drawn increasing attention. Therefore, the objective of this study was to assess the effectiveness of these phytochemicals in combating diabetes through a comprehensive evaluation of their interactions with biological networks through network pharmacology, molecular docking, and molecular dynamics simulations. The first goal of this study was to search and screen potential phytochemicals for binding with key proteins involved in T2DM, with special emphasis on AKT1 kinase, an integral component of the insulin signaling pathway. Network pharmacology analysis was carried out, and the interaction network of targets associated with T2DM was generated using KEGG, STRING and Cytoscape 3.9.1 software's. To determine the specific metabolic processes, cellular compartments, and molecular functions involved in T2DM, we performed Gene Ontology and KEGG analyses. An initial and short molecular docking study was conducted to analyze the binding modes, while the molecular dynamics simulations provided insights into the binding energy and stability of phytochemicals at target sites, with emphasis on rutin engaged with AKT1. In total, 10 hub genes were proposed to be involved in T2DM and can be considered candidate therapeutic targets, namely MTOR, CASP3, CCND1, TNF, MMP9, ALB, MDM2, AKT1, and HSP90AA1. Rutin was found to have the highest binding score for AKT1 in docking studies, while MD simulations identified the structural stability and persistence of the compound's activity at the target enzyme loci. This study identified rutin and flavonoids as potential anti-diabetes phytochemicals. Based on these observations, an opportunity for other in vitro experiments and additional in vivo studies to confirm these buildings as multi-target drugs in T2DM patients is provided.