In silico investigation and potential therapeutic approaches of isoquinoline alkaloids for neurodegenerative diseases: computer-aided drug design perspective

Abstract

Microtubule affinity regulating kinase (MARK4) has been proposed as a potential therapeutic target for diabetes, cancer, and neurological diseases. We used a variety of computational studies techniques to examine the binding affinity and MARK4 inhibitory potential of several isoquinoline alkaloids. MARK4 has been associated with tau protein phosphorylation and, consequently, Alzheimer’s disease. The three molecules with the highest binding affinities inside the 5ES1 receptor, according to molecular docking experiments, are isoliensinine, liensinine, and methylcorypalline. Isoliensinine had the highest drug score and drug likeness, coming in at 1.17, while Liensinine and Methylcorypalline came in at 1.15 and 1.07, respectively. The thesis claims that three compounds have a better chance than the others of being identified as therapeutic leads. The bulk of the compounds under investigation didn’t break any of Lipinski’s five rules, especially methylcorypalline, which did and is probably orally active. The majority of the compounds under investigation, particularly Isoliensinine, Liensinine, and Methylcorypalline, show the potential to exhibit drug-like behaviour, which is strongly confirmed by ADMET characteristics estimates. The chemicals Isoliensinine, Liensinine, and Methylcorypalline, especially Methylcorypalline, form the most stable combination with the 5ES1, according to a 100 ns molecular dynamics simulation of these compounds docked inside 5ES1 complexes. Methylcorypalline has a higher binding affinity inside 5ES1, according to additional MM/GBSA experiments using MD trajectories. Overall, research supports the use of the drug development tool methylcolipalin for its ability to inhibit MARK4, which may have implications for the treatment of neurodegenerative diseases.Communicated by Ramaswamy H. Sarma