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In silico Study of Potential Non-oxime Reactivator for Sarin-inhibited Human Acetylcholinesterase

Rauda A. Mohamed, Keat Khim Ong, Norhana Abdul Halim, Noor Azilah Mohd Kasim, Siti Aminah Mohd Noor, Victor Feizal Knight, Rabbani Muhamad and Wan Md Zin Wan Yunus

Pertanika Journal of Science & Technology, Volume 29, Issue 3, July 2021

DOI: https://doi.org/10.47836/pjst.29.3.19

Keywords: Antidote, docking, in silico, inhibition, organophosphate, oxime, reactivator, simulation

Published on: 31 July 2021

The search for new compounds other than oxime as potential reactivator that is effective upon organophosphate poisoning treatments is desired. The less efficacy of oxime treatment has been the core factor. Fourteen compounds have been screened via in silico approach for their potential as sarin-inhibited human acetylcholinesterase poisoning antidotes. The selection of the compounds to be synthesized based on this computational screening, reduces the time and cost needed. To perform the docking study of sarin-inhibited acetylcholinesterase and reactivator-sarin inhibited acetylcholinesterase complexations, a bioinformatics tool was used. Estimation of the nucleophilic attack distance and binding energy of fourteen potential compounds with sarin inhibited acetylcholinesterase complexes to determine their antidote capacities was carried out using Autodock. A commercially available antidote, 2-PAM was used for the comparison. The best docked-pose was further examined with molecular dynamics simulation. Apart from being lipophilic, a compound with a carboxylic acid, (R)-Boc-nipecotic acid is shown to exhibit 6.29 kcal/mol binding energy with 8.778 Å distance of nucleophilic attack. The stability and flexibility of the sarin-inhibited acetylcholinesterase, complexed with (R)-Boc-nipecotic acid suggests this compound should be tested experimentally as a new, promising antidote for sarin-inhibited acetylcholinesterase poisoning.

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