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CNS & Neurological Disorders - Drug Targets, 2014, 13, 265-270 265
A Neuroinformatics Study Describing Molecular Interaction of Cisplatin with Acetylcholinesterase: A Plausible Cause for Anticancer Drug Induced Neurotoxicity
Mohd Hassan Baig
1,§, Syed Mohd. Danish Rizvi
1,§, Shazi Shakil
*,2, Mohammad Amjad Kamal
3and Saif Khan
11Department of Biosciences, Integral University, Lucknow-226026, India
2Department of Bio-Engineering, Integral University, Lucknow-226026, India
3King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia
Abstract: Several chemotherapeutic drugs are known to cause significant clinical neurotoxicity, which can result in the early cessation of treatment. To identify and develop more effective means of neuroprotection it is important to understand the toxicity of these drugs at the molecular and cellular levels. This study describes molecular interactions between human brain acetylcholinesterase (AChE) and the well-known anti-neoplastic drug, Cisplatin. Docking between Cisplatin and AChE was performed using ‘GOLD 5.0’ and accessible surface area of protein before and after ligand binding was calculated by NACCESS version 2.1.1. Hydrophobic interactions and hydrogen bonds both play an equally important role in the correct positioning of Cisplatin within the ‘acyl pocket’ as well as ‘catalytic site’ of AChE to permit docking. Gold fitness score of ‘Cisplatin- acyl domain of AChE’ interaction and ‘Cisplatin-CAS domain of AChE’
interaction were 38.78 and 39.91, respectively and free binding energy was found to be -5.82 Kcal/mol and -5.79 Kcal/mol, respectively. During ‘Cisplatin-CAS site of AChE enzyme’ interaction, it was found that out of the three amino acids constituting the catalytic triad (S203, H447 and E334), two amino acid residues namely S203 and H447 interact with Cisplatin by hydrogen bonding and hydrophobic interaction, respectively. The values for ‘accessible surface area’ for the amino acid residues H447 and S203 were found to be reduced by 14.398 Å2 and 3.894 Å2, respectivelyafter interaction with Cisplatin. Hence, Cisplatin might act as a potent inhibitor of AChE. Scope still remains in the determination of the three-dimensional structure of AChE-Cisplatin complex by X-ray crystallography to validate the described data. Moreover, such information may aid in the design of versatile AChE-inhibitors, and is expected to aid in safe clinical use of Cisplatin.
Keywords: Acetylcholinesterase, cisplatin, docking, accessible surface area.
INTRODUCTION
Molecular docking studies are extensively being used to address issues pertaining to various research fields such as neurology [1], clinical microbiology [2], diabetology [3] and enzymology [4], to name a few. Cisplatin, cis-[Pt(II)(NH(3)) (2)Cl(2)] ([PtCl2(NH3)2] or Cis-diamminedichloroplatinum (CDDP) is one of the most potent chemotherapy drugs widely used for cancer treatment [5]. Cisplatin is found to be highly effective in the treatment of testicular and ovarian cancers and is also employed for treating bladder, cervical, head and neck, esophageal, and small cell lung cancer [6].
Despite the positive effects of Cisplatin, patients receiving this drug experience severe side effects that limit the dose which can be administered [5]. Side effects of platinum therapy include general cell-damaging effects, such as nausea and vomiting, decreased blood cell and platelet production in bone marrow (myelosuppresion) and decreased
*Address correspondence to this author at the Department of Bio-Engineering, Integral University, Lucknow, Lucknow, UP-226026, India;
Tel: 0522-2890812, 2890730, 3296117, 6451039; Fax: 0522-2890809;
E-mail: [email protected]
§Both the authors have equal contribution
response to infection (immunosuppression). More specific side effects include damage to the kidney (nephrotoxicity), damage of neurons (neurotoxicity) and hearing loss [7-11].
Cisplatin neurotoxicity is clinically evident in patients that have undergone a full course of chemotherapy which is first characterized by painful paresthesias and numbness that typically occurs during the first few drug cycles [12]. Further loss of vibration sense, paraesthesia, and ataxia become apparent after several treatment cycles [12]. Cisplatin seems to affect the axons, myelin sheath, neuronal cell body and the glial structures of the neurons [13]. However, it is generally accepted that binding of Cisplatin to genomic DNA (gDNA) in the cell nucleus is largely responsible for its antitumor properties [14] and the N7 atoms of the imidazole rings of guanine and adenine located in the major groove of the double helix are the most accessible and reactive nucleophilic sites for platinum binding to DNA [15]. This reaction of Cisplatin with DNA leads to the formation of various structurally different adducts in Dorsal Root Ganglion neurons at a given cumulative dose of Cisplatin.
This significantly correlates with the degree of neurotoxicity [16]. In another study, severity of neurotoxicity of Cisplatin and other platinum drug- Oxaliplatin was evaluated and it was observed that Cisplatin produced about three times more
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platinum-DNA adduct in the Dorsal Root Ganglion [17] than equimolar doses of oxaliplatin. This was consistent with the clinical observations that associated Cisplatin with greater neurotoxicity. However, the exact mechanism of the transition from a platinum-DNA adduct to neuronal apoptosis is not fully understood and it might be possible that there may be many other mechanisms responsible for Cisplatin neurotoxicity. As platinum compounds show strong reactivity against S-donor molecules, this may affect the activity of enzymes, receptors, and other proteins through binding to sulfur atoms of cysteine and/or methionine residues and to nitrogen atoms of histidine residues [18]. The resulting functional protein damage may also be responsible for the biochemical mechanism of Cisplatin neurotoxicity.
The present study, concerns with the enzyme acetylcholinesterase (AChE, EC 3.1.1.7), a serine hydrolase, which is primarily involved in the termination of chemical transmission at cholinergic synapses and secretory organs by catalyzing the hydrolysis of the neurotransmitter acetylcholine. Anticholinesterase substances (cholinesterase inhibitors) suppress this action of the enzyme [19]. These inhibitors are used in treatment of various neuromuscular disorders and have provided the first generation of drugs for treatment of Alzheimer’s disease (AD) [20]. On the other hand, they can become potent neurotoxins causing excessive salivation and eye-watering, followed by muscle spasms (sudden uncontrollable strong tightening of the muscles) and ultimately death [19]. To predict the mechanism of Cisplatin induced neuropathy we have attempted to investigate the inhibitory effect of Cisplastin on AChE.
Cisplatin was found to inhibit activity of camel retina and erythrocyte membrane-bound AChE in a concentration- dependent manner [21-23]. Another study [24] characterized human erythrocyte membrane-bound AChE inhibition by Cisplatin with respect to establishment of kinetic parameters at the reversible stage and found that Kiapp decreased while Vmaxiapp increased with increase in the acetylthiocholine (substrate) concentration. However, there is a paucity of information about the possible molecular interactions between the two (AChE and Cisplatin). Hence, the identification of the amino acid residues crucial to the interaction between human AChE and Cisplatin is of scientific interest. Such information is expected to aid in optimizing the safe and efficacious use of Cisplatin in patients. Furthermore, this study would be useful for scientists involved in drug design in their ongoing search for more potent and versatile AChE-inhibitors. Currently, no X- ray crystallographic structural data are available within the Protein Data Bank (PDB) to aid in the characterization of the interaction between AChE and Cisplatin. In our earlier study, we observed the inhibitory effect of cyclophosphamide (CP) and methotraxate on AChE enzyme and both the drugs were found to have significant interactions with the enzyme [25, 26]. Similarly, our present study describes the mode of potential interactions as well as the accessible surface area (ASA) of the residues (before and after the interaction) involved in accommodation of Cisplatin within the active site of AChE. This may underpin Cisplatin induced inhibition of human brain AChE.
METHODS
Preparation of Enzyme and Ligand for Docking
The three dimensional structure of recombinant human acetylcholinesterase was retrieved from protein databank (pdb id: 3LII). For the molecular docking calculations, the molecules of water, molecules of crystallization and hetero atoms were removed. CharMm [27] force field was applied to the structure of acetylcholinesterase followed by energy minimization for 1000 steps through steepest descent method at RMS gradient of 0.1 in Distance-Dependent Dielectrics type implicit solvent model. The 2D structure of Cisplatin was drawn using Chemdraw and was further converted into 3Dimensional structure in mol2 format. Cff forcefield was applied to this structure. The Cff forcefield is a general purpose class II forcefield, with good parameter coverage for many organic molecules. As a class II forcefield, it has additional cross terms in its potential energy function, compared to other class I forcefields.
Molecular Docking and Accessible Surface Area Calculation
To perform molecular docking, GOLD [28] (Genetic Optimization for Ligand Docking) 5.0 was used for docking of Cisplatin against selected human acetylcholinesterase.
Docking annealing parameters for van der Walls and hydrogen bonding were set to 5.0 and 2.5, respectively. The parameters used for genetic algorithm were population size 100, selection pressure 1.2, number of operations 1,00,000, number of islands 5, niche size 2, migrate 10, mutate 100 and cross -over 100. Differences in accessible surface area (ASA) of protein before and after ligand complex formations were calculated from NACCESS version 2.1.1 [29].
Accessible surface area, A, of an atom is the area on the surface of a sphere of radius R, on each point of which the center of a solvent molecule can be placed in contact with this atom without penetrating any other atom of the molecule. The radius R is given by the sum of the van der Waal’s radius of the atom and the chosen radius of the solvent molecule. An approximation to this area is computed by this program using the formula:
accessible surface area, A=Σ(R/ R2-Zi2).D.Li D=ΔZ/2+Δ’Z
where Li, is the length of the arc drawn on a given section i, Zi is the perpendicular distance from the center of the sphere to the section i, ΔZ is the spacing between the sections, and Δ’Z is ΔZ/2 or R-Zi, whichever is smaller. Summation is over all of the arcs drawn for the given atom. The accessibility is defined simply as the accessible surface area divided by 4πR2 and multiplied by 100. The binding energies of docked molecules were also calculated using X-score [30]. All molecular graphics material of docked complexes was prepared using pymol.
RESULTS AND DISCUSSION
The three dimensional structure of AChE can be compared to two hemispheres that sandwich the catalytic
Molecular Interaction of Cisplatin with Acetylcholinesterase CNS & Neurological Disorders - Drug Targets, 2014, Vol. 13, No. 2 267
center between the acyl- and omega-loops. These loops act as the sidewalls of the active site gorge that is approximately 300 Å3 in dimension [31, 32]. Three sub-sites within this active site gorge are noteworthy, (i) a ‘Peripheral Anionic Site’ or PAS at the gorge mouth that is the initial binding domain encountered by a substrate or inhibitor, (ii) a deeper cationic-π site (CAS), where the quaternary ammonium of choline of ACh interacts, (iii) a still deeper acylation site (that is the active center of the enzyme in which the catalytic triad constituted by serine, histidine and glutamate resides), is located at the bottom of a narrow 20- Å -deep gorge that penetrates halfway into the enzyme and widens close to its base and, (iv) the acyl-binding pocket located at the base of the gorge [31-34].
This study revealed the binding of Cisplatin within the active sites of AChE. The acyl pocket of human brain AChE was found to interact with Cisplatin through ten amino acid residues, namely S293, R296, Y341, W286, L289, V294, F295, F297, F338 and G342 (Fig. 1; Table 1). Seven amino acid residues (W286, L289, V294, F295, F297, F338 and G342) of AChE were found to be involved in hydrophobic interactions for the proper accommodation of Cisplatin within the acyl pocket of AChE. Moreover, three amino acid residues, namely S293, R296and Y341 of acyl pocket of AChE were found to make hydrogen bonds with Cisplatin.
Hence, a total of 3 hydrogen bonds and seven hydrophobic bonds were found crucial to the appropriate positioning of Cisplatin in the acyl pocket of human brain AChE. The quantification of the packing of residues in protein and docking of ligands to macromolecules is important in understanding protein stability and drug design. For a given number of partner atoms, a comparison of the observed ASA with the expected value obtained from the equation provides
a method of assessing the goodness of packing of the residue in a protein structure or its importance in the binding of a ligand [35]. The values for accessible surface area (ASA) on complex formation for each amino acid residue of acyl pocket of AChE (Table 2) were found to be W286 (64.952 Å2-82.621 Å2), L289 (32.983Å2-35.392Å2), S293 (7.616Å2- 27.556Å2), R296 (36.447Å2-39.515Å2), Y341 (39.397Å2- 65.838Å2), V294 (0.944Å2-5.744Å2), F295 (1.542Å2- 7.936Å2), F297 (8.208Å2-15.633Å2), F338 (8.182Å2- 14.282Å2) and G342 (39.582Å2-39.723Å2). This encompasses the “small,” “standard,” and “large” interface sizes as discussed by Lo Conte et al. [36] and thus represents a good sampling of the space of protein interfaces.
Fig. (1). Interaction of Cisplatin docked to the “acyl pocket” of the human brain acetylcholinesterase. Interacting side chains of AChE are shown in ‘stick’ format. Ligand (Cisplatin) is shown in ‘ball’
format. All amino acid residues crucial to the binding are labeled.
Table 1. Amino Acid Residues Involved in 'AChE-Cisplatin' Interactions
Active Sites Gold Fitness Score
Binding Free Energy (Kcal/mol)
Residues Involved
Hydrogen Bonding Hydrophobic Interactions
Acyl Pocket 38.78 -5.82 S293, R296, Y341 W286, L289, V294, F295, F297, F338, G342
Catalystic site/CAS 39.91 -5.79 E202, S203 W86, G120, G121, G122, A204, Y337, F338, H447, G448, Y449, I451
Table 2. Accessible Surface Area of Acyl Pocket Residues Before and After Binding of Cisplatin
Residues ASA (Prior Docking) ASA (Post Docking) Mean Change of ASA
W286 82.621 64.952 17.669
L289 35.392 32.983 2.409
S293 27.556 7.616 19.940
V294 5.744 0.944 4.800
F295 7.936 1.542 6.394
R296 39.515 36.447 3.068
F297 15.633 8.208 7.425
F338 14.282 8.182 6.100
Y341 65.838 39.397 26.441
G342 39.723 39.582 0.141
The CAS site of human brain AChE was found to interact with Cisplatin through 12 amino acid residues, namely W86, G120, G121, G122, Y337, F338, H447, G448, Y449, I451, E202 and S203 (Fig. 2; Table 1). Elaboration of these interactions might aid in the design of AChE inhibitors focused on the backbone of Cisplatin. Out of the twelve interacting amino acids residues of CAS pocket of AChE, ten amino acid residues (W86, G120, G121, G122, Y337, F338, H447, G448, Y449 and I451) were found to be involved in hydrophobic interaction and two amino acid residues (E202 and S203) were found to be involved in hydrogen bonding with Cisplatin. The values for accessible surface area (ASA) on complex formation for each amino acid residue of CAS pocket of AChE (Table 3) were found to be W86 (31.648Å2-48.123Å2), G120 (3.407Å2-6.583Å2), G121 (8.763Å2-22.763Å2), G122 (2.511Å2-3.097 Å2), Y337 (21.307Å2-40.42Å2), F338 (11.402Å2-14.282Å2), H447 (0.476Å2-14.874Å2), G448 (0.365Å2-2.819Å2), Y449 (3.821Å2-5.876 Å2), I451 (0.684Å2-1.941Å2), E202 (0.472Å2-8.233Å2)and S203 (2.593Å2-6.487Å2).
Gold fitness scores for ‘Cisplatin-acyl domain of AChE’
interaction and ‘Cisplatin- CAS domain of AChE’
interaction were found to be 38.78 and 39.91, respectively.
Rescoring the docked results using X-score, revealed that Cisplatin binds within these two active sites with binding free energies of -5.82 Kcal/mol and -5.79 Kcal/mol, respectively. From the results, it can be concluded that out of the three residues constituting the catalytic triad of human AChE enzyme, namely S203, H447 and E334 [31-33], two amino acid residues (S203 and H447) were found to interact with Cisplatin by hydrogen bonding and hydrophobic interaction, respectively, during ‘Cisplastin-CAS site of AChE enzyme’ interaction. Furthermore, the ASA values for these two amino acid residues after interaction with Cisplatin were found to be reduced by 14.398 Å2 and 3.894 Å2 for H447 and S203, respectively. This revealed that ‘post docking ASA’ in case of interaction of Cisplastin with H447 is much lesser than the same for interaction of Cisplastin with S203. These results were in contrast to the finding which stated that decrease in ASA with increase in partner
number took place more slowly for hydrophilic residues than for hydrophobic residues [35].
Fig. (2). Interaction of Cisplatin docked to the “catalytic site” or
“CAS” of the human brain acetylcholinesterase. Interacting side chains of AChE are shown in ‘stick’ format. Ligand (Cisplatin) is shown in ‘ball’ format. All amino acid residues crucial to the binding are labeled.
The total ASA of all the residues in uncomplexed Human AChE was 20018.679 Å2. The ASA was decreased to 19931.953 Å2 and 19937.026 Å2 when Cisplatin was bound to the Acyl and CAS site of AChE, respectively. Hence, the values for total change in ASA (∆ASA) for ‘Cisplatin-acyl site of AChE’ and ‘Cisplastin-CAS site of AChE’ interactions were found to be 86.726 Å2 and 81.653 Å2, respectively.
The present study reveals that Cisplatin is an efficient inhibitor of AChE in terms of amino acid interaction, gold fitness score, binding free energy and ∆ASA. Our results were in agreement with various in vitro studies which showed that Cisplatin inhibited Acetyl choline esterase activity [21-23]. In other in vitro studies, Cisplatin was used as an inducer of neurotoxicity in neuron cells [37, 38]. So, this study also provides a hope to predict one of the mechanisms of neuropathy caused by Cisplatin.
Table 3. Accessible Surface Area of CAS site residues before and after binding of Cisplatin
Residues ASA (Prior Docking) ASA (Post Docking) Mean Change of ASA
W86 48.123 31.648 16.475
G120 6.583 3.407 3.176
G121 22.763 8.763 14.000
G122 3.097 2.511 0.586
E202 8.233 0.472 7.761
S203 6.487 2.593 3.894
Y337 40.42 21.307 19.113
F338 14.282 11.402 2.880
H447 14.874 0.476 14.398
G448 2.819 0.365 2.454
Y449 5.876 3.821 2.055
I451 1.941 0.684 1.257
Molecular Interaction of Cisplatin with Acetylcholinesterase CNS & Neurological Disorders - Drug Targets, 2014, Vol. 13, No. 2 269
Further investigations are needed to address the issue regarding the ready entry of Cisplatin-concentrations into human brain tissues, high enough to inhibit AChE. The study is expected to aid future design of more specific and safer pharmacological compounds. Before closing the discussion we find it pertinent to mention that information about interacting amino acid residues and accessible surface area values obtained through computational studies can only suggest efficiency of binding for an enzyme-ligand pair.
However, it has been observed that the results of computational analyses often correlate well with the outcomes of experimental studies. Nevertheless, the trio consisting of 'computational', 'in vitro' and 'in vivo' studies with reference to the study enzyme (AChE) and ligand (Cisplatin) is expected to form the basis of future therapy against several neurological disorders.
CONCLUSION
This study explores molecular interactions between human brain AChE and the well-known anti-neoplastic drug, Cisplatin. Hydrophobic interactions and hydrogen bonds both play an equally important role in the correct positioning of Cisplatin within the ‘acyl pocket’ as well as ‘catalytic site’
of AChE to permit docking. However, docking of Cisplatin to AChE is largely dominated by hydrophobic interactions.
Such information may aid in the design of versatile AChE- inhibitors, as well as aid in the most efficacious and safe clinical use of Cisplatin. Scope remains in the determination of the three-dimensional structure of AChE-Cisplatin complex by X-ray crystallography to validate these data.
This study confirms that Cisplatin is an efficient inhibitor of human brain AChE with reference to its interaction with catalytic triad of AChE.
LIST OF ABBREVIATIONS AChE = Acetylcholinesterase CAS = Catalytic site
DNA = Deoxyribonucleic acid
GOLD = Genetic Optimization for Ligand Docking ASA = Accessible Surface Area
CONFLICT OF INTEREST
The authors confirm that this article content has no conflict of interest.
ACKNOWLEDGEMENTS Declared none.
REFERENCES
[1] Shakil S, Kamal MA, Tabrez S, et al. Molecular interaction of the antineoplastic drug, methotrexate with human brain acetylcholinesterase: a docking study. CNS Neurol Disord Drug Targets 2012; 11(2): 142-7.
[2] Shakil S. Addressing Clinical Microbiology Problems through Bioinformatics Tools. LAP Lambert Academic Publishing 2009.
[3] Shakil S, Khan AU. Infected foot ulcers in male and female diabetic patients: a clinico-bioinformative study. Ann Clin Microbiol Antimicrob 2010; 14(9): 2.
[4] Shakil S, Khan AU. Interaction of CTX-M-15 enzyme with cefotaxime: a molecular modelling and docking study.
Bioinformation 2010; 30; 4(10): 468-72.
[5] Florea AM, Büsselberg D. Metals and breast cancer: risk factors or healing agents? J Toxicol 2011; 2011: 159619.
[6] Giaccone G. Treatment of thymoma and thymic carcinoma. Ann Oncol 2000; 11(3): 245-6.
[7] Desoize B, Madoulet C. Particular aspects of platinum compounds used at present in cancer treatment. Crit Rev Oncol Hematol 2002;
42(3): 317-25.
[8] Shah N, Dizon DS. New-generation platinum agents for solid tumors. Future Oncol 2009; 5(1): 33-42.
[9] Günes DA, Florea AM, Splettstoesser F, Büsselberg D. Co- application of arsenic trioxide (As2O3) and Cisplatin (CDDP) on human SY-5Y neuroblastoma cells has differential effects on the intracellular calcium concentration ([Ca2+]i) and cytotoxicity.
Neurotoxicology 2009; 30(2): 194-202.
[10] Florea AM, Büsselberg D. Occurrence, use and potential toxic effects of metals and metal compounds. Biometals 2006; 19(4):
419-27.
[11] Tsang RY, Al-Fayea T, Au HJ. Cisplatin overdose: toxicities and management. Drug Saf 2009; 32(12): 1109-22.
[12] McWhinney SR, Goldberg RM, McLeod HL. Platinum neurotoxicity pharmacogenetics. Mol Cancer Ther 2009; 8(1): 10-6.
[13] Stillman M, Cata JP. Management of chemotherapy-induced peripheral neuropathy. Curr Pain Headache Rep 2006; 10(4): 279-87.
[14] Gonzalez VM, Fuertes MA, Alonso C, Perez JM. Is Cisplatin-induced cell death always produced by apoptosis? Mol Pharmacol 2001; 59(4):
657-63.
[15] Yang XL, Wang AHJ. Structural studies of atom-specific anticancer drugs acting on DNA. Pharmacol Ther 1999; 83: 181-215.
[16] Dzagnidze A, Katsarava Z, Makhalova J, et al. Repair capacity for platinum-DNA adducts determines the severity of Cisplatin-induced peripheral neuropathy. J Neurosci 2007; 27(35): 9451-7.
[17] Ta LE, Espeset L, Podratz J, Windebank AJ. Neurotoxicity of oxaliplatin and Cisplatin for dorsal root ganglion neurons correlates with platinum-DNA binding. Neurotoxicology 2006; 27(6): 992-1002.
[18] Perez RP. Cellular and molecular determinants of Cisplatin resistance. Eur J Cancer 1998; 34(10): 1535-42.
[19] Okoronkwo NE, Echeme JO, Onwuchekwa EC. Cholinesterase and bacterial inhibitory activities of Stachytarpheta cayennensis. Acad Res 2012; 2(3): 209-17.
[20] Greenblatt HM, Dvir H, Silman I, Sussman JL. Acetylcholines- terase: a multifaceted target for structure-based drug design of anticholinesterase agents for the treatment of Alzheimer's disease. J Mol Neurosci 2003; 20(3): 369-83.
[21] Al-Jafari AA, Kamal MA, Duhaiman AS. The mode of inhibition of human erythrocyte membrane-bound acetylcholinesterase by Cisplatin in vitro. J Enzyme Inhib 1995; 8(4): 281-9.
[22] Al-Jafari AA, Kamal MA, Alhomida AS. On the inhibition of camel retina acetylcholinesterase activity by cycloheximide in vitro. Cell Biol Toxicol 1998; 14(3): 167-74.
[23] Al-Jafari AA, Kamal MA. Investigation of the effect of tetrahydroaminoacridine on turnover kinetics of camel (Camelus dromedarius) retina acetylcholinesterase. Biochem Mol Biol Int 1996; 39(5): 917-22.
[24] Kamal MA. Characterization of human erythrocyte membrane- bound acetylcholinesterase inhibition by Cisplatin at reversible phase. Anticancer Res 1996; 16(6B): 3725-30.
[25] Shakil S, Khan R, Tabrez S, et al. Interaction of human brain acetylcholinesterase with cyclophosphamide: a molecular modeling and docking study. CNS Neurol Disord Drug Targets 2011; 10(7):
845-8.
[26] Shakil S, Kamal MA, Tabrez S, et al. Molecular interaction of the antineoplastic drug, methotrexate with human brain acetylcholine- esterase: a docking study. CNS Neurol Disord Drug Targets 2012;
11(2): 142-7.
[27] Brooks BR, Bruccoleri RE, Olafson BD, Swaminathan S, Karplus M. CHARMM: A program for macromolecular energy, minimizati- on, and dynamics calculations. J Comp Chem 2004; 4(2): 187-217.
[28] Jones G, Willett P, Glen RC. Molecular recognition of receptor sites using a genetic algorithim with a description of desolvation. J Mol Biol 1995; 245: 43-53.
[29] Hubbard SJ, Thornton JM. NACCESS, Computer Program, Department of Biochemistry and Molecular Biology; University College London 1993.
[30] Wang R, Lai L, Wang S. Further development and validation of empirical scoring functions for structure-based binding affinity prediction. J Comput Aided Mol Des 2002; 16(1): 11-26.
[31] Silman I, Sussman JL. Acetylcholinesterase: 'classical' and 'non- classical' functions and pharmacology. Curr Opin Pharmacol 2005;
5(3): 293-302.
[32] Silman I, Sussman JL. Acetylcholinesterase: how is structure related to function? Chem Biol Interact 2008; 175(1): 3-10.
[33] Sussman JL, Harel M, Frolow F, et al. Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein. Science 1991; 253(5022): 872-9.
[34] Raves ML, Harel M, Pang YP, et al. Structure of acetylcholinesterase complexed with the nootropic alkaloid, (-)- huperzine A. Nat Struct Biol 1997; 4(1): 57-63.
[35] Samanta U, Bahadur RP, Chakrabarti P. Quantifying the accessible surface area of protein residues in their local environment. Protein Eng 2002; 15(8): 659-67.
[36] Lo Conte L, Chothia C, Janin J. The atomic structure of protein- protein recognition sites. J Mol Biol 1999; 285(5): 2177-98.
[37] Song SQ, Zhang GN. Therapeutic evaluation of Cisplatin, etoposide, and bleomycin chemotherapy regimen in high-risk gestational trophoblastic neoplasia. Zhonghua Fu Chan Ke Za Zhi 2012; 47(8): 571-6.
[38] Mendonça LM, da Silva Machado C, Teixeira CC, et al. Curcumin reduces Cisplatin-induced neurotoxicity in NGF-differentiated PC12 cells. Neurotoxicology 2012; 34: 205-11.
Received: January 1, 2013 Revised: February 8, 2013 Accepted: February 13, 2013
PMID: 24059317