Plant derived active compounds of ayurvedic neurological formulation, Saraswatharishta as a potential dual leucine zipper kinase inhibitor: an in-silico study

• Published in: Journal of biomolecular structure & dynamics Vol. 42; no. 20; pp. 11201 - 11214
• Main Authors: Koirala, Suman, Roy, Rajarshi, Samanta, Sunanda, Mahapatra, Subhasmita, Kar, Parimal
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 06.12.2024
• Subjects: Binding Sites; Computer Simulation; dual leucine zipper kinase (DLK); Humans; Hydrogen Bonding; Leucine Zippers; MAP Kinase Kinase Kinases - antagonists & inhibitors; MAP Kinase Kinase Kinases - chemistry; MAP Kinase Kinase Kinases - metabolism; Medicine, Ayurvedic; Molecular Docking Simulation; molecular dynamics; Molecular Dynamics Simulation; Neurodegeneration; Phytochemicals - chemistry; Phytochemicals - pharmacology; Plant Extracts - chemistry; Plant Extracts - pharmacology; Protein Binding; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Saraswatharishta; virtual screening; Saraswatharishta; virtual screening; molecular dynamics; Neurodegeneration; dual leucine zipper kinase (DLK)
• ISSN: 0739-1102; 1538-0254; 1538-0254
• DOI: 10.1080/07391102.2023.2260892

Recent findings have highlighted the essential role of dual leucine zipper kinase (DLK) in neuronal degeneration. Saraswatharishta (SWRT), an ayurvedic formulation utilized in traditional Indian medicine, has demonstrated effectiveness in addressing neurodegenerative diseases. Herein, we aim to delve into the atomistic details of the mode of action of phytochemicals present in SWRT against DLK. Our screening process encompassed over 500 distinct phytochemicals derived from the main ingredients of the SWRT formulation. Through a comparative analysis of docking scores and relative poses, we successfully identified four novel compounds, which underwent further investigation via 2 × 500 ns long molecular dynamics (MD) simulations. Among the top four compounds, CID16066851 sourced from the Acorus calamus displayed the most stable complex with DLK. The molecular mechanics Poisson − Boltzmann surface area (MM-PBSA) calculations highlighted the significance of electrostatic and van der Waals interactions in the binding recognition process. Additionally, we identified key residues, namely Phe192, Leu243, Val139, and Leu141, as hotspots that predominantly govern the DLK-inhibitor interaction. Notably, the leading compounds are sourced from the Acorus calamus, Syzygium aromaticum, Zingiber officinale, and Anethum sowa plants present in the SWRT formulation. Overall, the findings of our study hold promise for future drug development endeavors combating neurodegenerative conditions. Communicated by Ramaswamy H. Sarma