Comparing the effect of Galantamine and Rivastigmine on beta-amyloid protein using docking method
Comparing the effect of Galantamine and Rivastigmine on beta-amyloid protein using docking method
Seyedeh Sara Ghorashi,1,*
1. Institute for Advanced Studies in Basic Sciences(IASBS) is an advanced research center and graduate-level degree-granting institution in Zanjan, Iran.
Introduction: Galantamine and Rivastigmine are cholinesterase inhibitors and are used to treat mild to moderate Alzheimer's disease. The main role of these drugs is to reduce the progression of clinical symptoms of Alzheimer's disease. In Alzheimer's disease, the central cholinergic neurons are disturbed due to the reduction of choline synthesis and its consumption. Cholinesterase inhibitors that reduce the breakdown of acetylcholine in the brain can be considered as a suitable drug.
One of the events of Alzheimer's disease is the deposition of different proteins in the brain of Alzheimer's patients. These proteins accumulate in the extracellular spaces in the form of amyloid deposits, one of these proteins is amyloid-beta. The reasons for the accumulation of amyloid-beta protein are the excessive production of this protein and the inability to remove amyloid-beta from the brain, which can be involved in the development of Alzheimer's disease.
In this investigation, a comparative study of the effect Galantamine and Rivastigmine, on beta-amyloid protein, which is involved in the formation and progression of Alzheimer's disease, has been done using the molecular docking method.
Methods: In this study, the website www.uniprot.org was used to investigate amyloid-beta protein. Also, used the pubchem.ncbi.nlm.nih.gov site to check the information of the drugs considered in this article. Chimera 1.15 and PyRx software were used for docking. At first saved amyloid-beta structure from a Uniprot site as a pdb file. Then the 3D structures of Galantamine and Rivastigmine drugs were saved in sdf format.
Specifications of Galantamine:
MF: C17H21NO3. Galantamine is a tertiary alkaloid and a competitive inhibitor of acetylcholinesterase enzyme, which is considered as a therapeutic target for Alzheimer's disease. Galantamine was extracted from botanical sources, such as Galanthus nivalis. As an inhibitor of acetylcholine, Galantamine prevents its breakdown in the synaptic space and increases its neurotransmission. This drug was approved by the FDA in 2001 for the treatment of mild to moderate Alzheimer's.
Specifications of Rivastigmine:
MF: C14H22N2O2. It is a reversible cholinesterase inhibitor. Rivastigmine is a carbamate ester and a tertiary amino compound. Rivastigmine is a parasympathomimetic or cholinergic agent for the treatment of mild to moderate dementia of the Alzheimer's type.
Editing of the target protein was done by Chimera 1.15 software. Amyloid-beta protein has 4 chains, in this study only chain A was examined and the rest of the chains were removed. Using this software, water molecules were removed from the structure and hydrogen molecules were added. After optimizing the structure, we used PyRx software to perform molecular docking and the gridbox was as follows:
scores centers
X= 0.992678 [95.41000366210938, 103.9000015258789, 208.07000732421875]
Y= 0.963918 [109.41000366210938, 107.9000015258789, 214.07000732421875]
Z= 0.71395 [91.41000366210938, 109.9000015258789, 174.07000732421875]
Results: After performing molecular docking for two drugs Galantamine and Rivastigmine, the results were obtained according to the following table:
RMSD upper bound RMSD lower bound Binding Affinity(kcal/mol) Galantamine
0.0 0.0 -6.0 Conformation 1
9.708 7.537 -5.8 Conformation 2
4.709 2.596 -5.8 Conformation 3
8.68 6.569 -5.8 Conformation 4
8.553 7.325 -5.7 Conformation 5
4.379 1.799 -5.7 Conformation 6
28.189 25.699 -5.6 Conformation 7
8.848 6.653 -5.6 Conformation 8
15.953 14.135 -5.6 Conformation 9
The result of Galantamine docking
RMSD upper bound RMSD lower bound Binding Affinity(kcal/mol) Rivastigmine
0.0 0.0 -5.0 Conformation 1
12.301 10.829 -4.7 Conformation 2
13.18 10.539 -4.7 Conformation 3
12.766 10.493 -4.5 Conformation 4
13.1 10.917 -4.5 Conformation 5
11.692 10.705 -4.5 Conformation 6
5.708 2.704 -4.4 Conformation 7
11.517 10.224 -4.4 Conformation 8
7.942 5.168 -4.4 Conformation 9
The result of Rivastigmine docking
Conclusion: According to the investigations, Conformation1 of Galantamine with negative binding affinity -6.0 and RMSD 0.0 has a better effect on amyloid-beta protein and preventing the progression of Alzheimer's disease.