An Insilico approach in Mitigation of the Diabetic complications caused by BDNF V66M variant

Author Name: *Malla Lalitha, Yadla Phani Kumar, A.Swaroopa Rani, Allam Apparao
Author Email: lalitharaj9@gmail.com

Abstract

Brain Derived Neurotropic Factor (BDNF) is a protein well recognized for its involvement in the growth and development of Neuronal system and synaptic plasticity. It plays a key role in Energy metabolism and Food intake. Studies were carried on the involvement of BDNF in the treatment of Diabetes and Obesity. The present study is on the specific variant V66M of BDNF protein and its influence on the pathways which are connected to the insulin signaling. This mutation leads to the decrease in the secretion of the mature BDNF. This will affect the activation of the TrkB receptor which is involved in the PI3k pathway in turn affecting the Insulin signaling. The complete analysis of the V66M variant was done. Through Computer aided drug designing approach, the chemical compound 1-(((2-((5-cyanopyridin-2-yl)amino)ethyl)amino)acetyl)-2-cyano-(s)-pyrrolidine was found to be the potent drug candidate which can mitigate the diabetic effect caused due to the mutation.

Keywords

Brain Derived Neurotropic Factor, insulin signaling, Computer aided drug designing

Introduction

Brain Derived Neurotropic Factor (BDNF) is a protein of Neurotropin family, a group of structurally related growth factors. The involvement of BDNF in insulin signaling can be connected with its regulation on TrkB receptor activation. Binding of BDNF with the TrkB Receptor plays a prominent role in intracellular signaling for neuronal survival, morphogenesis and plasticity; TrkB activation in turn elicits various Intracellular signaling pathways like mitogen activated protein kinase/ extracellular signal protein kinase (MAPK/ERK), Phospholipase Cg(PLCg) and phosphoinositide 3- Kinase (PI3K) pathway[1]. The PI3K has a major role in the insulin function via; activation of the AkT/ PkB and the PkCz cascades [2]. Therefore BDNF plays a prominent role in Glucose metabolism. The importance of this protein is further emphasized by suggesting its role in diabetes where patients with diabetes have found decreased concentration of BDNF. Both central and peripherally administered BDNF lowers blood glucose and increases energy expenditure in animal models of Type 2 Diabetes [3].
The variant at 66th position of BDNF has substitution mutation which changes the amino acid Valine to Methionine. This polymorphism affects the intracellular packaging of proBDNF and secretion of mature BDNF [4]. This leads to significant decrease in the BDNF Secretion. The mutation creates the disturbance in the interaction of ProBDNF with the sorting proteins thus leading to misorting of BDNF into the constitutive secretory pathway instead of regulated secretary pathway [5]. This mechanism will result in the decrease in concentration of Mature BDNF which affects the TrkB receptor activated pathways thus affecting the insulin signaling leading to Type 2 Diabetes. The current work aims at study the molecular details of the mutation and finding a potent drug candidate for mitigating the effect of this mutation in diabetes using an Insilico approach.

Conclusion

The work lays emphasis on the significance of the mutation V66M on molecular level. Drug Screening was performed to find the chemical compounds bearing the best drug property. By performing Docking studies , the chemical 1-(((2-((5-cyanopyridin-2-yl)amino)ethyl)amino)acetyl)-2-cyano-(S)-pyrrolidine was found to be the potent drug based on its best binding affinity which can be used in the treatment of Type 2 Diabetes.

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