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Investigations of the Key Binding Interactions of Novel Imidazole- and Benzimidazole-Based Oximes Within the Active Site of Butyrylcholinesterase


Primožič, Ines; Tomić, Srđanka; Hrenar, Tomica
Investigations of the Key Binding Interactions of Novel Imidazole- and Benzimidazole-Based Oximes Within the Active Site of Butyrylcholinesterase // Book of Abstracts of the Congress of the Croatian Society of Biochemistry and Molecular Biology "The Interplay of Biomolecules", HDBMB 2014 / Katalinić, M. ; Kovarik, Z. (ur.).
Zagreb: Croatian Society of Biochemistry and Molecular Biology, 2014. str. 124-124 (poster, nije recenziran, sažetak, znanstveni)


Naslov
Investigations of the Key Binding Interactions of Novel Imidazole- and Benzimidazole-Based Oximes Within the Active Site of Butyrylcholinesterase

Autori
Primožič, Ines ; Tomić, Srđanka ; Hrenar, Tomica

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Book of Abstracts of the Congress of the Croatian Society of Biochemistry and Molecular Biology "The Interplay of Biomolecules", HDBMB 2014 / Katalinić, M. ; Kovarik, Z. - Zagreb : Croatian Society of Biochemistry and Molecular Biology, 2014, 124-124

ISBN
978-953-95551-5-1

Skup
The Congress of the Croatian Society of Biochemistry and Molecular Biology "The Interplay of Biomolecules", HDBMB 2014

Mjesto i datum
Zadar, Hrvatska, 24-27.09.2014

Vrsta sudjelovanja
Poster

Vrsta recenzije
Nije recenziran

Ključne riječi
Human butyrylcholinesterase; inhibition; reactivation; oximes

Sažetak
Organophosphorus compounds can act as cholinesterase inhibitors and thus are used as pesticides, insecticides and nerve agents (soman, sarin, tabun, VX). The best antidotes for organophosphorus poisoning are oximes which antidotal properties are related to their ability to reactivate phosphorilated acetylcholinesterase (AChE, EC 3.1.1.7). Butyrylcholinesterase (BChE, EC 3.1.1.8) can be used for the treatment of organophosphorus poisoning as a stoichiometric bioscavenger. Applied with the BChE reactivator would make this enzyme even better treatment drug. [1, 2] Since there is still no single, broad-spectrum compound suitable as antidote for treatment of poisoning with various organophosphorus agents, search for more efficient oximes and better understanding of their interactions with both cholinesterases are needed. Therefore, a series of novel imidazole- and benzimidazole-2-aldoximes were tested as potential reactivators of paraoxone, tabun and VX inhibited human serum BChE. Imidazole and bezimidazole-2-aldoximes were alkylated with different alkyl, alkenyl as well as arylalkyl groups and 34 new compounds were prepared. All prepared oximes inhibited human BChE reversibly, and the inhibition potency was nanomolar (ponetial pre-treatment drugs) to micromolar. Reactivation power was also related to the structure of substituents, percentage varied from ten to ninety. To explain differences in inhibition and oximes reactivation potency, conformational analysis, molecular modelling and docking studies were carried out. Orientations of all studied oximes in the active site of human BChE have been proposed by flexible ligand docking and subsequent QM/QM studies. Analyses of the obtained complexes revealed the presence of numerous hydrogen bonds and close contacts between oximes and residues of the active site. Calculated interaction energies predicted correctly the relative order of the inhibition potency of compounds as well the most probable orientation of the best reactivators which can result in an attack on the phosphorus atom of VX and tabun-phosphorylated human BChE. [1] Radić Z., Dale T., Kovarik Z., Berend S., Garcia E., Zhang L., Amitai G., Green C., Radić B., Duggan B. M., Ajami D., Rebek, J. Jr., Taylor, P. Biochemical journal 450 (2013) 231-242. [2] Radić, Z., Sit R. K., Kovarik Z., Berend S., Garcia E., Zhang L., Amitai G., Green C., Radić B., Fokin V. V., Sharpless K. B., Taylor P. The Journal of biological chemistry 287 (2012) 11798-11809.

Izvorni jezik
Engleski

Znanstvena područja
Kemija



POVEZANOST RADA


Ustanove
Prirodoslovno-matematički fakultet, Zagreb