In Silico Molecular Docking Analysis of Karanjin against Alzheimer's and Parkinson's Diseases as a Potential Natural Lead Molecule for New Drug Design, Development and Therapy.

• Published in: Molecules
• Main Authors: Gnanaraj, Charles, Sekar, Mahendran, Fuloria, Shivkanya, Swain, Shasank S, Gan, Siew Hua, Chidambaram, Kumarappan, Rani, Nur Najihah Izzati Mat, Balan, Tavamani, Stephenie, Sarah, Lum, Pei Teng, Jeyabalan, Srikanth, Begum, M Yasmin, Chandramohan, Vivek, Thangavelu, Lakshmi, Subramaniyan, Vetriselvan, Fuloria, Neeraj Kumar
• Format: Article in Journal/Newspaper
• Language: English
• Published: MDPI 2022
• Subjects: ADMET; Alzheimer’s disease; Lipinski’s rule; Parkinson’s disease; bioinformatics; drug-likeness; in silico; karanjin; molecular dynamics; Orca
• Online Access: https://doi.org/10.3390/molecules27092834; https://pubmed.ncbi.nlm.nih.gov/35566187; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9100660/

Parkinson's disease (PD) and Alzheimer's disease (AD) are neurodegenerative disorders that have emerged as among the serious health problems of the 21st century. The medications currently available to treat AD and PD have limited efficacy and are associated with side effects. Natural products are one of the most vital and conservative sources of medicines for treating neurological problems. Karanjin is a furanoflavonoid, isolated mainly from Pongamia pinnata with several medicinal plants, and has been reported for numerous health benefits. However, the effect of karanjin on AD and PD has not yet been systematically investigated. To evaluate the neuroprotective effect of karanjin, extensive in silico studies starting with molecular docking against five putative targets for AD and four targets for PD were conducted. The findings were compared with three standard drugs using Auto Dock 4.1 and Molegro Virtual Docker software. Additionally, the physiochemical properties (Lipinski rule of five), drug-likeness and parameters including absorption, distribution, metabolism, elimination and toxicity (ADMET) profiles of karanjin were also studied. The molecular dynamics (MD) simulations were performed with two selective karanjin docking complexes to analyze the dynamic behaviors and binding free energy at 100 ns time scale. In addition, frontier molecular orbitals (FMOs) and density-functional theory (DFT) were also investigated from computational quantum mechanism perspectives using the Avogadro-ORCA 1.2.0 platform. Karanjin complies with all five of Lipinski's drug-likeness rules with suitable ADMET profiles for therapeutic use. The docking scores (kcal/mol) showed comparatively higher potency against AD and PD associated targets than currently used standard drugs. Overall, the potential binding affinity from molecular docking, static thermodynamics feature from MD-simulation and other multiparametric drug-ability profiles suggest that karanjin could be considered as a suitable therapeutic lead for AD and PD treatment. Furthermore, the present results were strongly correlated with the earlier study on karanjin in an Alzheimer's animal model. However, necessary in vivo studies, clinical trials, bioavailability, permeability and safe dose administration, etc. must be required to use karanjin as a potential drug against AD and PD treatment, where the in silico results are more helpful to accelerate the drug development.