INSILICO METHOD FOR PREDICTION OF MAXIMUM BINDING AFFINITY AND LIGAND – PROTEIN INTERACTION STUDIES ON ALZHEIMER’S DISEASE
Keywords:Molecular Docking, Alzheimer’s Disease, Acetylcholinesterase, ADME Analysis, Ligand-Protein Interactions
The aim of this study is to perform the molecular docking, identifying the drug likeness, ADME properties of drugs, Ligand-Protein interactions using different softwares. Due to the excess activity of Acetylcholinesterase, plaque formation and tau protein aggregation in the brain is the main cause for the Alzheimer’s disease. The interaction of Donepezil, Rivastigmine and Chlorzoxazone against AChE protein crystal structure (4EY5, 4EY6, 4EY7) using molecular docking were analyzed. Docking results of Rivastigmine and Chlorzoxazone were compared with Donepezil (widely used drug for Alzheimer’s disease) to identify the binding affinity. To verify whether Chlorzoxazone could act similarly as effective drug of Donepezil and also finding in which protein structure, ligands could bind effectively were employed using BIOVIA Discovery Studio software. Among those ligands interaction with all protein structure, 4EY7 on Rivastigmine (-7.1 kcal/mol) exhibits maximum binding affinity. The interactions of three ligands were compared with one another, in that Hydrogen bond formation of Chlorzoxazone and Donepezil with 4EY6 and 4EY7 interacting the similar aminoacids residues (4EY6-ARG165; 4EY7-ASP74) were studied using insilico studies .
Sheikh Arslan sehgal, Mirza A.Hammad , Rana Adnan Tahir, Hafiza Nisha Akram and Faheem Ahmad - Current therapeutics molecules and targets in Neurodegenerative disease based on In-silico drug design. 2018, 16, 649-663.
Kaliappan Ganesan - (Docking study of Benzothiazole – Piperazines: Ache Inhibitors for Alzheimer disease. 2017, 19, Pages: 103-107.
Shivani kumar, Suman Chowdhury and Suresh kumar. In-silico repurposing of antipsychotic drugs for Alzheimer disease. 2017, 18;76. DOI: https://doi.org/10.1186/s12868-017-0394-8
Chaudhary A, Maurya PK, Yadav BS, Singh S, Mani A. Current therapeutic Targets for Alzheimer's Disease. 2018, 3:74-84. DOI: https://doi.org/10.7150/jbm.26783
Martyn JAJ, Fagerlund MJ, Eriksson LI, Basic principles of neuromuscular transmission, Anaesthesia, 64, 2009, 1-9. DOI: https://doi.org/10.1111/j.1365-2044.2008.05865.x
Cheung J, Rudolph MJ, Burshteyn F, Cassidy MS, Gary MS, Love J, Franklin MC, Height JJ, Structures of human acetylcholinesterase in complex with pharmacologically important ligands, J. Med. Chem., 55, 2012, 10282–10286.
Dvir H, Silman I, Harel M, Rosenberry TL, Sussman JL, Acetylcholinesterase: From 3D Structure to Function, Chem. Biol. Interact., 187, 2010, 10-22. DOI: https://doi.org/10.1016/j.cbi.2010.01.042
Colovic MB, Krstic DZ, Lazarevic- Pasti TD, Bondzic AM, Vasic VM, Acetylcholinesterase Inhibitors: Pharmacology and Toxicology, Current Neuropharmacology, 11, 2013, 315-335. DOI: https://doi.org/10.2174/1570159X11311030006
Li JK, Zhang J, Rodrigues MC, Ding DJ, Longo JPF, Azevedo RB, Muehlmann LA, Jiang CS, Synthesis and evaluation of novel 1,2,3- triazole-based acetylcholinesterase inhibitors with neuroprotective activity, Bioorganic & Medicinal Chemistry Letters, 26, 2016, 3881– 3885. DOI: https://doi.org/10.1016/j.bmcl.2016.07.017
Quinn DM, Acetylcholinesterase: enzyme structure, reaction dynamics, and virtual transition states, Chem. Rev., 87, 1987, 955– 975. DOI: https://doi.org/10.1021/cr00081a005
Lipinski A, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational ap-proaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Del Rev 23: 3–25. DOI: https://doi.org/10.1016/S0169-409X(96)00423-1
Ballard CG, Advances in the treatment of Alzheimer’s disease: benefits of dual cholinesterase inhibition, Eur. Neurol., 47, 2002, 64–70. DOI: https://doi.org/10.1159/000047952
Mehta M, Adem A, Sabbagh M, New Acetylcholinesterase inhibitors for alzheimer's disease, Int. J. Alzheimers. Dis., 2012, 728983. DOI: https://doi.org/10.1155/2012/728983
Munoz-Torrero D, Acetylcholinesterase inhibitors as disease modifying therapies for alzheimer's disease, Curr. Med. Chem., 15, 2008, 2433-2455. DOI: https://doi.org/10.2174/092986708785909067
Jain AN, Scoring functions for protein-ligand docking, Curr. Protein Pept. Sci., 7, 2006, 407-420. DOI: https://doi.org/10.2174/138920306778559395
Dickerson TJ, Beuscher AE IV, Rogers CJ, Hixon MS, Yamamoto N, Xu Y, Olson AJ, Janda KD. Discovery of Acetylcholinesterase peripheral anionic site ligands through computational refinement of a directed library. Biochemistry. 2005; 44(45):14845–53. DOI: https://doi.org/10.1021/bi051613x
Hung-Jin Huang, Cheng-Chun Lee and Calvin Yu-Chian Chen. Insilico design of BACE1 inhibitor for Alzheimer disease by Traditional Chinese Medicine. 2014; 741703. DOI: https://doi.org/10.1155/2014/741703
Hardy J, Selkoe DJ (2002) Medicine - the amyloid hypothesis of alzheimer’s disease: Progress and problems on the road to therapeutics. Science 297: 353– 356. DOI: https://doi.org/10.1126/science.1072994
Aguzzi A, O’Connor T (2010) Protein aggregation diseases: pathogenicity and therapeutic per-spectives. Nat Rev Dru 9: 237–248. DOI: https://doi.org/10.1038/nrd3050
Hawkes CA, Ng V, MacLaurin J (2009) Small molecule inhibitors of alpha-beta aggregation and neurotoxicity. Drug Dev Res 70: 111–124. DOI: https://doi.org/10.1002/ddr.20290
Lahiri DK, Farlow MR, Sambamurti K, Greig NH, Giacobini E, Schneider LS (2003) A critical analysis of new molecular targets and strategies for drug developments in Alzheimer’s disease. Current drug targets 4: 97–112. DOI: https://doi.org/10.2174/1389450033346957
Cheung J, Rudolph MJ, Burshteyn F, Cassidy MS, Gary EN, Love J, et al. (2012) Structures of human acetylcholinesterase in complex with pharmacologically important ligands. Journal of medicinal chemistry 55: 10282–10286. DOI: https://doi.org/10.1021/jm300871x
Auriacombe S., J.J. Pere, Y. Loria-Kanza, B. Vellas, Efficacy and safety of rivastigmine in patients with Alzheimer’s disease who failed to benefit from treatment with donepenzil, Curr. Med. Res. Opin. 18 (3) (2002) 129–138. DOI: https://doi.org/10.1185/030079902125000471
McGleenon B.M., K.B. Dynan, A.P. Passmore, Acetylcholinesterase inhibitors in Alzheimer’s disease, Br. J. Clin. Pharmacol. 48 (4) (1999) 471–480. DOI: https://doi.org/10.1046/j.1365-2125.1999.00026.x
Kryger G., I. Silman, J.L. Sussman, Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design for the new anti-Alzheimer drugs, Structure 7 (1999) 297–307.
Mohamed T., P.P.N. Rao, Alzheimer’s disease: emerging trends in small molecule therapies, Curr. Med. Chem. 18 (28) (2011) 4299–4320.