Targeting Dihydrolipoamide Dehydrogenase (DLD) Interactors for Novel Therapeutic Interventions for Alzheimer’s Disease

Abstract

Alzheimer's disease is the one of the most common type of dementia, which affects millions of people worldwide. Severe memory loss is a defining feature, with episodic memory being particularly damaged in the initial stages. The majority of occurrences of Alzheimer's disease are random, while risk is increased if specific susceptibility genes are inherited. Alzheimer's disease is linked to a decline in energy metabolism, but it is unclear whether this decline worsens or prevents the condition. The finding that genetically dihydrolipoamide dehydrogenase (DLD) is associated to the late-onset AD serves as further evidence for the significance of energy metabolism in AD. To determine if DLD is an appropriate therapeutic target, in silico tools have been used in our study to analyse the interaction of DLD with CAND1, LAMP1, and TPP1 using molecular docking and visualization tools like PyRx, PyMOL, Discovery Studio, and Ligplot++. It was observed that binding sites of 5NHG are surrounded by 68 amino acids, and CAND1 (1191-1200), LAMP1 (216-225), and TPP1 (546-555) were able to interact with the amino acids inside the binding pocket of 5NHG. Protein network analysis showed aberration towards apoptosis. In our study, we also evaluated the binding of ascorbic acid, acetaminophen, and methamphetamine after docking experiment to find therapeutic potential. Ascorbic acid and acetaminophen showed the highest binding energy with 5NHG. The interaction of these drug compounds with 5NHG yielding high binding affinity shows that these compounds can be used to block the binding sites on DLD to prevent the interaction of pathological proteins with DLD that are involved in the up-regulation or down-regulation of DLD in diseased state.