Influence of gauche effect on uncharged oxime reactivators for the reactivation of tabun-inhibited AChE: quantum chemical and steered molecular dynamics studies.
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.
['Ghosh|Shibaji|S|', 'Jana|Kalyanashis|K|', 'Ganguly|Bishwajit|B|0000-0002-9858-3165']
D000110:Acetylcholinesterase D020134:Catalytic Domain D002800:Cholinesterase Inhibitors D002801:Cholinesterase Reactivators D006860:Hydrogen Bonding D057927:Hydrophobic and Hydrophilic Interactions D056004:Molecular Dynamics Simulation D010755:Organophosphates D010091:Oximes D011789:Quantum Theory D013329:Structure-Activity Relationship D013816:Thermodynamics
Gauche effect Tabun-inhibited AChE DFT Steered molecular dynamics and MM–PBSA