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
