Integrated Biological Regulatory Network and Molecular Modeling Pipeline for the Target Fishing and Therapeutic Intervention against Diabetes Type II

Abstract

Genetics factors in general play an important role in the development of diabetes. Several studies have linked the various gene mutations with development of type 2 diabetes. These gene mutations along with environment and other lifestyle factors may increase the risk. Some of the gene mutations and dysregulations have been reported in type 2 diabetes in Pakistan. These includes, HHEX, IDE, KCNJ11, NOTCH2, WFS1, IRS1, CAPN10, KCNQ1, HNF4A, HNF1B, IRS2, TCF7L2, GCG, RAGE, VEGF, MTNR1B, GLIS3, PPARG, NR4A1, CYR61. Nevertheless, the Genes involved in diabetes reported in general are VEGFA, NOS3, ABCA1, TCF7L2, ABCC8, CAPN10, GLUT2, GCGR, AGTR1, TNFA, IL6, amongst others. Several studies have reported biological networks or pathways to probe the key genes and proteins that are involved in the development and progression of diabetes. The major focus of these studies was the identification of the general biomarkers and thus, the therapeutic interventions against these identified biomarkers might have some better efficacy and toxicity profiles when used against a specific population. In this study, we aim to select potential genes and associated mutations that are associated with diabetes in the Pakistani population for personalized therapeutic intervention for the Pakistani population. Herein, BRN was dynamically simulated for target fishing which resulted in two proteins GLUT4 and PPARy as potential targets. Subsequently, Molecular dynamics simulations was used to probe the design of the therapeutic intervention against the selected protein target and drugs that are being used for diabetes type 2. And the targeted drugs were decided from docking results that which drugs are differentially expressed against mutations in Pakistani population and then for further validation and stability MD simulations were performed for 100ns. As a result, we concluded that Metformin, Oseni and Lobeglitazone are drugs which are 17 differentially expressed and stable. Overall, the study could pave the way towards personalized diabetic medicine against the Pakistani population