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Influence of gauche effect on uncharged oxime reactivators for the reactivation of tabun-inhibited AChE: quantum chemical and steered molecular dynamics studies

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Abstract

The neutral oxime reactivator RS194B with a seven-membered ring has shown better efficacy towards the tabun-inhibited AChE than that of RS69N with a six-membered ring and RS41A with a five-membered ring. The difference in the efficacy of these reactivators has remained unexplored. We report here the origin of the difference of efficacy of these reactivators based on the conformational analysis, quantum chemical calculations and steered molecular dynamics (SMD) simulations. The conformational analysis using B3LYP/6-31G(d) level of theory revealed that RS41A and RS194B are more stable in gauche conformation due to the gauche effect (–N–C–C–N– bonds) whereas RS69N prefers anti-conformation. The SMD simulations show that RS194B retains in more stable gauche conformation inside the active gorge of AChE during different time intervals that experiences more hydrogen bonding, hydrophobic interactions with the catalytic anionic site (CAS) residues and weaker interactions with the peripheral anionic site (PAS) residues compared to RS41A and RS69N. In an effort to design an even superior reactivator, RS194B-S has been chosen with a subtle change in the geometry of RS194B by replacing the carbonyl oxygen with the sulfur atom. The newly designed reactivator RS194B-S can also be a promising candidate to reactivate tabun-inhibited AChE.

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Acknowledgements

CSIR-CSMCRI Registration no: 123/2017. Shibaji Ghosh acknowledges AcSIR and CSIR-CSMCRI for providing him the opportunity for the doctoral research program. KJ is thankful to UGC New Delhi, India for awarding him senior research fellowship and AcSIR for providing him the opportunity for the doctoral program. BG thanks (DBT and DST), New Delhi for financial support. We are also thankful to the reviewer for valuable suggestions and comments that have helped us to improve the paper.

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  1. Computation and Simulation Unit (Analytical Discipline and Centralized Instrument Facility), CSIR-Central Salt and Marine Chemicals Research Institute, Bhavnagar, Gujarat, 364 002, India

    Shibaji Ghosh, Kalyanashis Jana & Bishwajit Ganguly

  2. Academy of Scientific and Innovative Research, CSIR-CSMCRI, Bhavnagar, Gujarat, 364 002, India

    Shibaji Ghosh, Kalyanashis Jana & Bishwajit Ganguly

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  1. Shibaji Ghosh
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Ghosh, S., Jana, K. & Ganguly, B. Influence of gauche effect on uncharged oxime reactivators for the reactivation of tabun-inhibited AChE: quantum chemical and steered molecular dynamics studies. J Comput Aided Mol Des 32, 793–807 (2018). https://doi.org/10.1007/s10822-018-0130-1

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