In silico investigation on understanding the molecular mechanism of antidiabetic activity by natural products through docking and molecular dynamics simulations

Abstract

Diabetes Mellitus, a multifactorial disorder is a major health concern and one of the greatest challenges of the modern era. Diabetes mainly occurs when, the pancreas does not produce enough insulin or when the body cannot effectively use the insulin it produces due to and#946;-cell dysfunction. Insulin is produced from the pancreatic and#946;-cells in response to the blood glucose levels and exhibits its physiological action of glucose uptake in skeletal muscles thorough insulin signaling pathway. Hence, the production of proper insulin and maintaining its cellular activity has been of therapeutic importance for glucose homeostasis to overcome diabetes. Various computational methods have been extensively used in drug design and discovery towards in-depth understanding of existing drugs and their mechanism, in order to design more potential and effective lead compounds. Along with experimental studies, computational techniques have been useful in determining the crucial atomistic interactions and structural mechanism facilitating their activity. Based on these strategies, many protein targets have gained clinical importance for the development of drugs against diabetes. Protein Tyrosine Phosphatase 1B (PTP1B) is one such major antidiabetic target based on its vital role in insulin signaling in adipose tissues by acting as negative regulator of the tyrosine kinase receptors. Though potent catalytic site inhibitors have been recognized, they mostly fail to advance beyond the pre-clinical stage due to their specificity to PTP1B from other members of PTP family. Allosteric site identification in PTP1B has made an alternative tactic in the development of PTP1B targeted therapy.The current study investigated the molecular interactions of six structurally different natural compounds Chlorogenic acid (CGA), Cichoric acid (CHA), Aloe emodin glycoside (AEG), 3ß-taraxerol (3BT), (3ß)-stigmast-5-en-3-ol (SGS) and methyl lignocerate (MLG) for their interactions with PTP1B. These compounds exhibited potential antidiabetic and antiadipogenic