In silico targeting of CYP19A1 and PTPN1 by Nigellidine: A network-based exploration of its antidiabetic pathway interactions

Abstract

Type 2 diabetes mellitus (T2DM) is a common metabolic health problem that is seen across the world with high levels of complications like cardiovascular disease, nephropathy and neuropathy. Nigellidine is an alkaloid of Nigella sativa and has shown good pharmacological potential. The integrative in silico strategy was used in this work and included the ADME/toxicity forecasting, network pharmacology, PPI analysis, and pathway enrichment. Also, molecular docking and molecular dynamics simulations were performed to determine important molecular targets and pathways that Nigellidine can influence to maintain T2DM. The structural and physicochemical properties of Nigellidine were obtained in PubChem and evaluated through Swiss ADME to achieve the drug-likeness. Swiss Target Prediction was used to predict potential molecular targets, and DisGeNET was used to get T2DM-related genes. Venn analysis was used to find similar targets. STRING was used to construct a protein-protein interaction (PPI) network that was analyzed in Cytoscape. hub genes were enriched by Gene Ontology (GO) and pathway analysis, KEGG, using DAVID. To measure binding affinities Molecular docking and dynamic simulation were carried out. Nigellidine exhibited good drug-like properties, having a molecular weight of 294.35 g/mol and TPSA of 47.16 Ų. It was identified to have 15 common targets, each of which was a central node, such as CYP19A1, PTPN1 and HSD11B1. These were associated with insulin signalling, glucose metabolism, and inflammation using GO and KEGG analyses. Docking was very much affinity-wise to CYP19A1 (-9.45 kcal/mol), PTPN1 (-9.05 kcal/mol), and HSD11B1 (-8.84 kcal/mol). Nigellidine has been shown to be a dynamically favorable endlessly stabilized complex with CYP19A1. This in silico integrated study indicates that Nigellidine has multi-targeted antidiabetic effects, and it should be examined further preclinically and clinically to manage T2DM.