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Revealing the importance of linkers in K-series oxime reactivators for tabun-inhibited AChE using quantum chemical, docking and SMD studies

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Abstract

Inhibition of acetylcholinesterase (AChE) with organophosphorus compounds has a detrimental effect on human life. Oxime K203 seems to be one of the promising reactivators for tabun-inhibited AChE than (K027, K127, and K628). These reactivators differ only in the linker units between the two pyridinium rings. The conformational analyses performed with quantum chemical RHF/6-31G* level for K027, K127, K203 and K628 showed that the minimum energy conformers have different orientations of the active and peripheral pyridinium rings for these reactivator molecules. K203 with (–CH2–CH=CH–CH2–) linker unit possesses more open conformation compared to the other reactivators. Such orientation of K203 experiences favorable interaction with the surrounding residues of catalytic anionic site (CAS) and peripheral anionic site (PAS) of tabun-inhibited AChE. From the steered molecular dynamics simulations, it has been observed that the oxygen atom of the oxime group of K203 reactivator approaches nearest to the P-atom of the SUN203 (3.75 Å) at lower time scales (less than ~1000 ps) as compared to the other reactivators. K203 experiences less number of hydrophobic interaction with the PAS residues which is suggested to be an important factor for the efficient reactivation process. In addition, K203 crates large number of H-bonding with CAS residues SUN203, Phe295, Tyr337, Phe338 and His447. K203 barely changes its conformation during the SMD simulation process and hence the energy penalty to adopt any other conformation is minimal in this case as compared to the other reactivators. The molecular mechanics and Poisson–Boltzmann surface area binding energies obtained for the interaction of K203 inside the gorge of tabun inhibited AChE is substantially higher (−290.2 kcal/mol) than the corresponding K628 reactivator (−260.4 kcal/mol), which also possess unsaturated aromatic linker unit.

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Acknowledgements

CSIR-CSMCRI Registration No: 122/2016. Shibaji Ghosh acknowledges AcSIR and CSIR-CSMCRI for providing him the opportunity for the doctoral research program. NBC is thankful to CSIR New Delhi, India for awarding him senior research fellowship and AcSIR for providing him the opportunity for the doctoral 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 (MSM, SIP, CSIR, New Delhi) and Department of Atomic Energy-Board of Research in Nuclear Sciences, Mumbai for financial support. We thank Dr. Suman Chakrabarty and Dr. Tushar Bandyopadhyay for helpful discussion. We are also thankful to the reviewer for valuable suggestions and comments that have helped us to improve the paper.

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Authors and Affiliations

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

    Shibaji Ghosh, Nellore Bhanu Chandar, Kalyanashis Jana & Bishwajit Ganguly

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

    Shibaji Ghosh, Nellore Bhanu Chandar, Kalyanashis Jana & Bishwajit Ganguly

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  1. Shibaji Ghosh
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Correspondence to Bishwajit Ganguly.

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Ghosh, S., Chandar, N.B., Jana, K. et al. Revealing the importance of linkers in K-series oxime reactivators for tabun-inhibited AChE using quantum chemical, docking and SMD studies. J Comput Aided Mol Des 31, 729–742 (2017). https://doi.org/10.1007/s10822-017-0036-3

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