Structure-guided screening identified bioactive phytoconstituents Hernandonine and Anolobine as potential inhibitors of dual specificity protein kinase CLK1.

Neurodegenerative diseases such as Alzheimer's disease (AD) are becoming a global health concern because of their progressive nature and the extent of the disability they cause to the affected individuals. Existing therapies for neurodegenerative diseases are primarily limited to symptomatic management and have shown diminishing efficacy over time, often leading to resistance. Therefore, there is an urgent need for novel therapeutic interventions that offer improved effectiveness with fewer side effects. A promising approach that has been suggested in neurodegenerative diseases, especially AD, is the prevention of tau phosphorylation by using kinase inhibitors. CDC2-like kinase 1 (CLK1) is a dual-specificity proline-directed protein kinase that is involved in both tau phosphorylation and splicing regulation and is thus a potential drug target. Currently, there are several small molecular CLK1 inhibitors, but problems like drug resistance and side effects still exist. In this study, we have used a structure-guided virtual screening approach to screen the bioactive phytoconstituents of Indian medicinal plants for potential CLK1 inhibitors. The systematic virtual screening involving molecular docking, density functional theory (DFT), and pharmacokinetic profiling, pinpointed Hernandonine and Anolobine as promising compounds due to their druglike properties and high binding affinity with CLK1. To assess the stability and interaction of these compounds with CLK1, all-atom molecular dynamics (MD) simulations and essential dynamics were performed for 500 ns. The results indicate that Hernandonine and Anolobine have a high potential for CLK1 inhibition and can be used as promising leads for developing novel effective drugs against neurodegeneration. This work underlines the importance of the combined use of virtual screening and MD simulations in the search for phytochemical-based CLK1 inhibitors, which can lead to the development of new therapeutic approaches in the treatment of neurodegenerative diseases such as AD.