CHARACTERIZATION OF PUTATIVE DRUGS FOR TARGETING ALZHEIMER'S DISEASE AND TYPE II DIABETES MELLITUS

Abstract

Alzheimer’s disease (AD) is an incurable and debilitating neurodegenerative disease, characterized by amyloid-beta (Aβ) agglomeration and tau hyperphosphorylation which is further accountable for the formation of senile plaques thereby causing synaptic loss. Mounting evidences have revealed an interlink between AD Type II diabetes mellitus (T2DM). T2DM is an age-related disease characterised by hyperglycemia, hyperinsulinemia and insulin resistance (IR), along with the incapability of utilizing glucose as an energy currency. The strong association between AD and T2DM suggests a shared pathology like cognitive impairment, mitochondrial dysfunction, and reactive oxygen species (ROS) production and thus provide a platform to explore the therapeutic potential of proteins shared between the two diseases. Since, the two well-known major proteins namely, Insulin degrading enzyme (IDE) and Neprilysin (NEP) has reportedly been involved in the degradation of Aβ peptides and insulin respectively therefore, provides a substantial evidence for the connective link between AD and T2DM. Further, normal expression of these proteins in the neuron is beneficial for normal homeostasis of brain because of its peptidase activity. On the contrary, its higher expression causes severe damage to the cells thereby leading to the advancement of oncogenic processes. Thus 10 controlling the level of these proteins is quite necessary for maintaining the homeostatic balance of neuronal cells. In current work, we have attempted to investigate the important biomolecles like curcumin, apomorphine, nobiletin, resveratrol, and norepinephrine that could maintain or regulate the levels of IDE and NEP to decline the chances of rapid onset of AD and T2DM. These biomolecules have an inevitable role to escalate the levels of IDE and NEP and most importantly, in the clearance mechanism to degrade the Aβ plaques. For this purpose, we have employed various in silico methods such as drug-likeliness parameters namely Lipinski filter analysis, Ghose parameters, Veber rules, ADMET analysis, active site prediction and molecular docking studies. Finally, the present study outlines the novel potential of these biomolecules in regulating both the IDE and NEP expression to attenuate the neuronal loss.