A neuroinformatics study describing molecular interaction of Cisplatin with acetylcholinesterase: a plausible cause for anticancer drug induced neurotoxicity.

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 Å(2) and 3.894 Å(2), respectively after 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.