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COMPUTER-ASSISTED DRUG DESIGN OF DONEPEZIL ANALOGUES FOR ALZHEIMER’S DISEASE Sai Lakshmi.Palla*1, N.Dugnath*2, Manoj Kumar Mahto*3 *1,2,3 N.
Duganath, Department of Pharmaceutical Chemistry, Oil Technological Research Institute, Jawaharlal Nehru Technological University, Anantapur, Andhra Pradesh, India515001.
ABSTRACT Alzheimer's disease is a progressive disorder that causes brain cells to degenerate and die. Alzheimer’s disease is characterized by loss of neurons and synapses in the cerebral cortex and certain sub cortical regions. Alzheimer's disease is the most common cause of dementia a continuous decline in thinking, behavioral and social skills that disrupts a person's ability to function independently. Donepezil inhibit the acetylcholinesterase which degrades the acetylcholine transmitter. Computer Assisted Drug designing is used for the introduction of new therapeutic analogues of Donepezil. Energy minimization for analogues is done by using hyperchem software. Docking of the protein-ligand complex was done by using GOLD software. Present study includes new lead identification for Alzheimer’s disease, inhibiting the function of Acetyl cholinesterase protein, molecular docking studies. Binding affinity calculations by using molecular docking studies including computer aided drug design followed by molecular mechanics based binding affinity calculations. Keywords: Donepezil, Acetylcholinesterase, Binding affinity, Molecular docking, Molecular mechanics.
I.
INTRODUCTION
Bioinformatics is a management information system for molecular biology. Applications of Bioinformatics involve sequence analysis, molecular evolution, genome mapping database query tools and comparison, gene identification, structure prediction, drug designing and drug target identification. Computerassisted drug design (CADD), also called computer-assisted molecular design (CAMD) and represents more recent applications of computers as tools in the drug design process. In most current applications of CADD, attempts are made to find a ligand (the putative drug) that will interact favorably with a receptor that represents the target site. Binding of Ligand to the receptor may include hydrophobic, electrostatic, and hydrogen-bonding interactions. Ligand based drug design is applicable when the structure of the receptor site is unknown, but when a series of compounds have been identified that exert the activity of interest. Receptor based drug design1 incorporates several molecular modeling techniques, one of which is docking. Docking allows scoring based on force fields, which include both Vander Waals and electrostatic interactions. These results illustrate the potential for docking programs to search objectively for ligand than are complementary to receptor sites, thereby assisting researchers in identifying potential drugs than may be considerably different from existing drugs. The term molecular mechanics refer to the use of Newtonian mechanics to model molecular systems. Molecular mechanics have properties like each atom is stimulated as a single particle, each particle is assigned a radius, polarizability and constant net charge. MM+ is designed to reproduce the equilibrium covalent geometry of molecules as precisely as possible. AMBER is a family of force fields for molecular dynamics. The standard AMBER force field is parameterized to small organic constituents of proteins and nucleic acids. Energy minimization2 methods can precisely locate minimum energy conformations by mathematically “homing in” on the energy function minima.
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Fig.-1: Hypothetical energy surface The goal of energy minimization is to find a route from an initial conformation to the nearest minimum energy conformation using the smallest number of calculations possible. Molecular dynamics3 is carried out to anneal the system to obtain a lower energy minimum. They calculate the future positions and velocities of atoms based upon their current values. Protein-ligand docking4 is done by modelling the interaction between protein and ligand, if the geometry of the pair is complementary and involves favorable biochemical interactions, the ligand will potentially bind the protein invitro or in vivo. The QSAR equation is a linear model, which relates variations in biological activity to variations in the values of computed properties for a series of molecules. Alzheimer's disease (AD) 6 is a brain disease that slowly destroys memory and thinking skills and, eventually, the ability to carry out the simplest tasks. Dementia is generally defined as the ‘loss of intellectual abilities (medically called cognitive function) like loss of thinking, remembering, and reasoning skills that interferes with a person's daily life and activities.
Fig.-2: Healthy brain and Alzheimer’s advanced Two pathological characteristics are observed in AD patients at autopsy: extracellular plaques and intracellular tangles in the hippocampus, cerebral cortex, and other areas of the brain essential for cognitive function.5 the key event leading to AD appears to be the formation of a peptide known as amyloidal beta which clusters into amyloidal plaques on the blood vessels and on the outside surface of neurons of the brain which ultimately leads to the killing of neurons.
Fig.-3: Amyloidal plaques www.irjmets.com
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Currently there are more than 100 clinical trials being conducted in Alzheimer’s and dementia. The government requires that all new medicines undergo rigorous testing in the laboratory, first in animals and then in human volunteers, before they can be prescribed by doctor or sold in pharmacies. Once the required clinical trials are completed, companies submit an application to the FDA, the government agency responsible for the safety of foods and drugs sold in U.S. together with an independent panel of medical advisors, the FDA reviews the scientific data and determines whether the drug is safe and effective for people with Alzheimer’s. NMDA7 antagonist, is prescribed to treat moderate to severe Alzheimer’s disease. Acetyl cholinesterase8 is an enzyme that degrades the neurotransmitter acetylcholine , producing choline and an acetate group. Donepezil9 enhances cholinergic transmission by reducing the enzymatic degradation of acetylcholine. Donepezil is 1200 times more selective for acetyl cholinesterase rather than butyl cholinesterase. Donepezil gives a short-term improvement in cognitive function but does not appear to alter the underlying disease process. Bioinformatics was an emerging field with the potential to significantly improve how drugs are found, brought to clinical trials and eventually released to the marketplace. The main aim of doing CADD: •
CADD enable comparative study of the analogues and help us in analyzing relative superiority of the analogues to the initial drug itself.
•
Computer-assisted molecular design (CAMD) represents more recent applications of computers as tools in the drug design process.
•
Extensive literature studies were undertaken to scrutinize methods involved in computer aided drug designing.
•
National and international journal, news and conference reviews also patents available on drug designing of Alzheimer’s were searched from available web sites.
II.
METHODOLOGY
The present study was to design and identify the potent novel acetyl cholinesterase inhibitors in the treatment of Alzheimer’s disease using Insilco tools and techniques.
Based on above scheme select the disease to that select target protein and collect the protein reports from PDB. Compute protein energy minimization. Select the lead moiety and design the ligands/analogs for lead moiety. Compute energy minimization and note down molecular properties. Dock the ligand analogs and minimized protein. From that we can determine the binding affinity of analogs. www.irjmets.com
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MODELING AND ANALYSIS
The software’s used for design of drug analogs are Hyperchem and GOLD( Genetic Optimization for ligand Docking). Hyperchem is a molecular modeler and editor and a powerful computational technique. Hyperchem used to build and display molecules, optimizing the structure of molecules and studying the dynamic behavior of molecules.
Fig.-4: HyperChem software for design of drug analogs Computational molecular docking is a research technique for predicting whether one molecule will bind to another, usually a protein. Protein -protein, protein-DNA and protein-ligand docking prediction is all performed by using Hyperchem software.
Fig.-5: Docking study with HyperChem GOLD used in virtual screening, lead optimization, and identifying the correct binding mode of active molecules. GOLD uses genetic sequence to provide docking of flexible ligand and a protein with hydroxy groups. This makes GOLD is the good choice when the binding pocket contains amino acids that form hydrogen bonds with the ligand. GOLD offers a scoring functions: GOLD score, Chem Score and User defined Score. The solutions are known to have 70-80% accuracy when tested on complexes extracted from PDB.
Fig.-6: GOLD- Protein Ligand Docking Software www.irjmets.com
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Following steps are involved in Donepezil analog study: 1.Determining the analogs and energy optimization a) b) c) d) e) f)
Force field Selection(AMBER) Analog Selection(Donepezil) Single Point Energy Calculation(energy or spin density) Geometry Optimization(energy of analogs optimized) Molecular Mechanics Optimization(Polak-Ribiere) Measuring Intramolecular parameters(bond length, bond angle, torsion angle)
2. Dynamic calculations a) Molecular dynamic calculations 3. Optimization of Solvents a) b) c) d) e) f)
Adding periodic box(simulate behavior of molecules in aqueous solution) Molecular Mechanics force field(AMBER) Optimization by selecting only the Hydrogens Optimization by selecting only water molecules Optimization by selecting active region(modified hydrophobic region)of ligand Optimization for the ligand molecule in its solvated state
4. Optimization in various force fields(bond length, bond angle, torsion angles) 5. Optimization of protein-ligand complexes(target for donepezil is acetyl cholinesterase having enzyme code 1EVE) 6. Docking a) Preparing input for Docking b) Docking(using GOLD software)
IV.
RESULTS AND DISCUSSION
Donepezil Ligand R-CH3 is replaced with different ligands like R-NH2, R-CH2CH3, R-OH, R-Cl and R-H. Energy minimization of different ligand moieties are given in the table. Table-1 Ligand-R-CH3
Single point
Energy
Gradient
Converge
1816.160 kcal/mol
1092.113kcal/A0mol
Yes
Geometry optimization
31.81 kcal/mol
0.000931 kcal/A0mol
Yes
Single point
Energy
Gradient
Converge
1687.42 kcal/mol
1096.983kcal/A0mol
Yes
31.24 kcal/mol
0.000849 kcal/A0mol
Yes
Fig No 7 Ligand-R-NH2
Geometry optimization Fig No 8
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Single point
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Energy
Gradient
Converge
1812.94 kcal/mol
1060.493 kcal/A0mol
Yes
Geometry optimization
32.965kcal/mol
0.001000kcal/A0mol
Yes
Single point
Energy
Gradient
Converge
Fig No 9 Ligand-R-OH
kcal/A0mol
1736.90 kcal/mol
1108.02
Yes
Geometry optimization
31.182 kcal/mol
0.000940 kcal/A0mol
Yes
Single point
Energy
Gradient
Converge
Fig No 10 Ligand-R-Cl
kcal/A0mol
1851.67 kcal/mol
1125.52
Yes
Geometry optimization
32.00 kcal/mol
0.000968 kcal/A0mol
Yes
Single point
Energy
Gradient
Converge
1642.78 kcal/mol
116.74 kcal/A0mol
Yes
29.45 kcal/mol
0.000993kcal/A0mol
Yes
Fig No 11 Ligand-R-H
Geometry optimization Fig No 12
Table-2: Ligand in periodic box: Ligand-R-CH3
Selected atoms
Hydrog ens
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Geometry optimization Steepest descent(500)
Polakribier(2000cycles)
Energy
Gradient
Conver ge
Energy
Gradien t
Conver ge
8836.19kcal /mol
0.76kcal/A0 mol
No
-1073.36
0.00098 8 kcal/A0 mol
Yes
kcal/mol
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Whole molecul e
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1073.36kcal /mol
0.000988 kcal/A0mol
1073.36kcal /mol
0.000988 kcal/A0mol
No
No
www.irjmets.com 1073.36kcal /mol
0.00098 8
1073.36kcal /mol
0.00098 8 kcal/A0 mol
Yes
kcal/A0 mol Yes
Table-3 Ligand-R-NH2
Selected atoms
Hydrog ens
Geometry optimization Steepest descent(500)
Polakribier(2000cycles)
Energy
Gradient
Conver ge
Energy
Gradient
Converge
7092.24kcal /mol
1.251kcal/A0 mol
No
8861.4 8
0.166
Yes
kcal/A0 mol
kcal/m ol
Fig No:14 Ligands
8864.81kcal /mol
0.064
No
kcal/A0mol
8878.3 5 kcal/m ol
Whole molecul e
-8878.35
0.001000
kcal/mol
kcal/A0mol
No
8878.3 5 kcal/m ol
Selected atoms Ligand-RCH2CH3
Hydrog ens
0.00100 0
Yes
kcal/A0 mol 0.00100 0
Yes
kcal/A0 mol
Geometry optimization Steepest descent(500)
Polakribier(2000cycles)
Energy
Gradient
Conver ge
Energy
Gradient
Conver ge
6800.60kcal/ mol
0.815kcal/A0 mol
No
8474.6 7
0.038
Yes
kcal/A0m ol
kcal/m ol Ligands Fig No: 15
8474.83kcal/ mol
0.015 kcal/A0mol
No
8476.1 19
0.000992
Yes
kcal/A0m ol
kcal/m www.irjmets.com
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Whole molecul e
-8476.12
0.000992
kcal/mol
kcal/A0mol
No
8476.1 2
0.000992
Yes
kcal/A0m ol
kcal/m ol Table-5 Ligand-R-OH
Selected atoms
Hydroge ns
Geometry optimization Steepest descent(500)
Polakribier(2000cycles)
Energy
Gradient
Conver ge
Energy
Gradient
Conver ge
11558.16kcal/ mol
2.167kcal/A0 mol
No
1440.3 69
0.0495
Yes
kcal/A0 mol
kcal/m ol
Fig No: 16 Ligands
1440.725kcal/ mol
0.0164
No
kcal/A0mol
14402. 02 kcal/m ol
Whole molecul e
-1440.016
0.000988
kcal/mol
kcal/A0mol
No
1440.0 16 kcal/m ol
0.00098 8
Yes
kcal/A0 mol 0.00098 8
Yes
kcal/A0 mol
Table-6 Ligand-R-Cl
Selected atoms
Hydroge ns Fig No:17
Geometry optimization Steepest descent(500)
Polakribier(2000cycles)
Energy
Gradient
Conver ge
Energy
Gradient
Conver ge
8744.14kcal/ mol
2.0871kcal/A0 mol
No
10736. 17
0.127
Yes
kcal/A0 mol
kcal/m ol Ligands
10738.41kcal/ mol
0.029 kcal/A0mol
No
1077.1 42 kcal/m
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0.00097 4
Yes
kcal/A0 mol
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Whole molecul e
-1077.142
0.000974
kcal/mol
kcal/A0mol
No
1077.1 42 kcal/m ol
0.00097 4
Yes
kcal/A0 mol
Table-7 Ligand-R-H
Fig No: 18
Selected atoms
Geometry optimization Steepest descent(500)
Hydroge ns
Polakribier(2000cycles)
Energy
Gradient
Conver ge
Energy
Gradient
Conver ge
14198.96kcal/ mol
2.233kcal/A0 mol
No
174.00 34
0.19170 7
Yes
kcal/m ol Ligands
17450.26kcal/ mol
0.0384
No
1759.6 79
kcal/A0mol
kcal/A0 mol 0.0069
Yes
kcal/A0 mol
kcal/m ol Whole molecul e
-1759.689
0.0069
kcal/mol
kcal/A0mol
No
1759.6 89 kcal/m ol
0.00097 8
Yes
kcal/A0 mol
Table-8: Solvated Ligand Donepezil Ligand R-NH2
R-NH2
Force field MM+
Force field Amber-99
Energy
23.77 kcal/A0mol
44.434kcal/A0mol
Gradient
0.000899kcal/A0mol
0.000949 kcal/A0mol
Converge
Yes(766 points)
Yes(642 points)
cycles 1684
cycles
1399
Fig No: 19 Table-9 Donepezil R-CH2CH3
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R-CH2CH3
Force field MM+
Force field Amber-99
Energy
25.98 kcal/A0mol
42.119 kcal/A0mol
Gradient
0.002044 kcal/A0mol
0.000975kcal/A0mol
Converge
Yes(855 1905points)
Yes(709 points)
cycles
cycles
1545
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Fig No:20 Table-10 Donepezil R-OH
R-OH
Force field MM+
Force field Amber-99
Energy
21.44 kcal/mol
42.83 kcal/mol
Gradient
0.000821 kcal/A0mol
0.000985 kcal/A0mol
Converge
Yes(651 points)
Yes(608 1301points)
cycles
1651
cycles
Fig No:21 Table-11 Donepezil R-Cl
R-Cl
Force field MM+
Force field Amber-99
Energy
22.89 kcal/A0mol
8.20 kcal/A0mol
Gradient
0.006264 kcal/A0mol
0.020493kcal/A0mol
Converge
Yes(855 4281points)
Yes(1456 cycles 3212 points)
cycles
Fig No: 22 Table-12 Donepezil R-H
R-H
Force field MM+
Force field Amber-99
Energy
20.93 kcal/A0mol
6.26 kcal/A0mol
Gradient
0.007079 kcal/A0mol
0.000961 kcal/A0mol
Converge
Yes(855 cycles 2106 points)
Yes(794 points)
cycles 1727
Fig No:23 Table-13: Binding Energy calculation: S.no
Ligand
X1(energy of ligand in medium of air)
X2(energy of solvated ligand)
X=X1+(-X2)
1
-CH3
31.81
42.80
-10.99
2
-NH2
31.24
44.34
-13.1
3
-CH2CH3
32.97
42.119
-9.149
4
-OH
31.18
42.83
-11.648
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5
-Cl
32.00
39.33
-7.33
6
-H
29.45
28.78
0.67
Table-14: Protein with modified ligand Donepezil R-CH3
Geometry optimization (polak) Energy
Gradient
Converge
Whole protein
-13698.32 kcal/mol
0.734 kcal/A0mol
Yes
Ligand
-14.91 kcal/mol
0.000994 kcal/A0mol
Yes
Donepezil R-NH2
Geometry optimization (polak)
Fig No:24
Energy
Gradient
Converge
Whole protein
-5056.50 kcal/mol
0.22043 kcal/A0mol
Yes
Ligand
-13.32 kcal/mol
0.00092 kcal/A0mol
Yes
Donepezil R-CH2CH3
Geometry optimization (polak)
Fig No:25
Energy
Gradient
Converge
Whole protein
6124.43kcal/mol
0.3114 kcal/A0mol
Yes
Ligand
-15.11 kcal/mol
0.000998 kcal/A0mol
Yes
Donepezil R-OH
Geometry optimization (polak)
Fig No:26
Energy
Gradient
Converge
Fig No:27 www.irjmets.com
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Whole protein
-6533.18 kcal/mol
0.32 kcal/A0mol
Yes
Ligand
-12.86 kcal/mol
0.000995 kcal/A0mol
Yes
Donepezil R-Cl
Geometry optimization (Polak) Energy
Gradient
Converge
Whole protein
-5056.68 kcal/mol
0.22kcal/A0mol
Yes
Ligand
-13.73kcal/mol
0.000924 kcal/A0mol
Yes
Donepezil R-H
Geometry optimization (Polak)
Fig No:28
Energy
Gradient
Converge
Whole protein
-4625.62kcal/mol
0.335 kcal/A0mol
Yes
Ligand
-12.36 kcal/mol
0.000863 kcal/A0mol
Yes
Fig No:29
Protein for Docking
Fig.-30: Acetyl Cholinesterase Protein Table-15 Energy
Gradient
Converged
-1556 kcal/mol
0.000952 kcal/A0mol
Yes
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Table-16: Ligand for Docking Ligand
Energy
Gradient
Converge
R-NH2
35.06 kcal/mol
0.000952 kcal/A0mol
Yes (955 2086points)
cycles
R-CH3
38.60kcal/mol
0.000997 kcal/A0mol
Yes (183 410points)
cycles
R-CH2CH3
37.97 kcal/mol
0.000807 kcal/A0mol
Yes (135 cycles 314 points)
R-OH
34.30 kcal/mol
0.000960 kcal/A0mol
Yes (807 cycles 1712 points)
R-Cl
38.35 kcal/mol
0.000984 kcal/A0mol
Yes (37 points)
R-H
33.98 kcal/mol
0.000957 kcal/A0mol
Yes (968 points)
cycles
84
cycles 2106
Table-17 S. No
Ligands
Fitness
S(hb-ext)
S(vdw-ext)
S(hb-int)
S(vdw-int)
1
-CH3
60.68
0.28
52.43
0.00
-11.69
2
-NH2
65.47
4.63
48.90
0.00
-6.41
3
-CH2CH3
69.11
0.00
54.53
0.00
-5.86
4
-OH
52.62
4.10
47.12
0.00
-6.27
5
-C1
61.11
5.55
46.26
0.00
-8.05
6
-H
49.54
0.01
50.72
0.00
-20.21
Table-18 S.no
Ligand
Y1
(-)Y2
Y=Y1+Y2
1
-CH3
-14.91
(-)60.68
-75.59
2
-NH2
-13.32
(-)65.4575
-78.7775
3
-CH2CH3
-15.11
(-)64.99375
-80.10375
4
-OH
-12.86
(-)62.62
-75.48
5
-C1
-13.73
(-)61.1075
-74.8375
6
-H
-12.36
(-)49.54
-61.876
Y1=Protein intra dock Y2=Docking energy Table-19 S.no
Ligand
Y
X
Z=Y-X
1
-CH3
-75.59
-10.99
-64.6
2
-NH2
-78.7775
-13.1
-65.6775
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3
-CH2CH3
-80.10375
-9.149
-70.95475
4
-OH
-75.48
-11.648
-63.832
5
-C1
-74.8375
-7.33
-67.5075
6
-H
-61.876
0.67
-62.546
Table-26 Relative binding free energy S.no
Molecules
Relative binding free energy
1
-NH2
-1.07
2
-CH2CH3
-6.35475
3
-OH
0.768
4
-C1
2.054
5
-H
-2.9075
Through rational based drug design approach, new analogs are designed by replacing pharmacophore groups (which are having tendency to bond with target protein) in ligand. Docking is performed with the optimized analogs and protein and binding energy was calculated for each analog. The analog with R group –CH2CH3 in Donepezil having lowest binding free energy -6.35475 will have maximum binding affinity.
V.
CONCLUSION
Based on energy minimization, force field calculations and protein ligand docking studies of structurally similar analogs of Donepezil indicates that molecular mechanics methods gave suitable analogs. Molecular mechanics-based methods for calculation of relative binding affinities can be used before synthesis and biochemical testing of new analogs. The drug Donepezil with substituent R= -CH2CH3 is identified as the most suitable analog in the present study and needs to be further evaluated in laboratory.
VI. [1]
[2] [3]
[4] [5] [6] [7] [8] [9]
REFERENCES
Trinchado R.(2000) Docking of phosphonate and trehalose analog inhibitors into M. Tuberculosis Mycolic Transferase Ag85C. Comparison of the two scoring fitness functions Gold Score and Chem Score .J.GOLD software.1095-122. Bar beau(1988) A. Manganese and extra pyramidal disorders (a critical review and tribute to Dr. George C. Cotijas).J. Neurotoxicology. 5(1):13-35. Benito-Leon J, Bermejo-Pareja F, Morales-Gonzalez J, Porta- Etessam, J,Trincado, R,Louis (2000)Incidence of Parkinson disease and parkinsonism in three elderly populations of central Spain. J. Neurology. 62(5):734-41. Bermejo F(1988) Problems and issues with door to door, two phase surveys: An illustration from central Spain.J.Neuroepidemiology.20-225. Ozelius, L, Senthil, G, Lipton, R, Soto-Valencia ,J, Risch, N, Bressman, N. Engle(1985) S.LRRK2G2019S as a cause of Parkinson’s disease in Ashkenazi Jews. J. Med.354(4):425-5. Parkinson J(1984).An essay on the shaking palsy. J. Neuropsychiatry Clin Neurosis. 354(4):22336. M. K. York, H. S. Levin, R. J. Grossman, W. J. Hamilton, N Brain.(2000) neuropsychological outcome following unilateral pallidotomy. 122(12):2209-2220. O. Horny Kiewicz(2000) L-DOPA. Biologically inactive amino acid to a successful therapeutic agent. Institute for brain research, university of Vienna. 48:1605-1610. A Brice.(1987) Genetics of Parkinson’s disease. J . Brain. 128(12):2760-2762.
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