Investigation on the Binding Affinities of Different Anthelmintic Drugs on the 3D Model Protein Structure of Acetylcholinesterase of Schistosoma mansoni: An in silico Approach

Objective: Acetylcholinesterase (AchE) is an important neurotransmitter enzyme that helps in the motility of helminth parasites. In view of functional significance, the present study was designed to predict three dimensional (3D) structure of Schistosoma mansoni AchE and study the binding affinity of ten anthelmintics with the model protein. Methods: Protein models were generated using Modeller9v10, taking 2PM8 template protein. PROCHECK, ANOLEA and ERRAT tools were used to validate the model proteins. Anthelmintics-albendazole (ABZ), artemether (ART), benzimidazole (BZD), diethylcarbamazine (DEC), levamisole (LEV), mebendazole (MBZ), praziquantel (PZQ), oxamniquine (OXA), metrifonate and phosphonic amides were studied for its binding affinity against the modeled protein using Molegro Virtual Docker taking two natural AchE-inhibitors, eserine and tetra-isopropyl pyro phosphamide as a reference drug. Similarly, identification of the lead compound among all the 12 ligands has also been performed using PharmaGist. Results: Five model proteins were generated in this present study. Out of the 5 homology protein models, model protein number 5 was chosen to be best on the basis of the result of various validation tools used. Ligand binding pockets search by CASTp showed a total 152 pockets with best pocket with an area and volume 2964.8 and 6480.3Å, respectively. Superpositions and multiple flexible alignments of a random set of 10, 5 and 3 annotated ligands by the server generated tetra-isopropyl pyro phosphamide, ABZ and MBZ as the lead compounds amongst all ligands. Superimposition of 3 annotated ligands revealed MBZ the best pharmacophore ligand with top score 22.35. Docking studies showed MBZ having the highest binding affinity followed by ABZ and PZQ. Reference drugs showed similar kind of affinity with the model protein. Conclusion: The present study appears to provide greater inside about the functioning of AchE of S. mansoni and its interaction with different anthelmintic drugs.

Author(s): Ananta Swargiary and Akalesh Kumar Verma

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