Acetylcholinesterase (AChE) reactivation rates for current nucleophilic reactivators (oximes) are relatively slow even for the best compounds under the most favorable conditions. Many factors contribute to this observation among them are off target binding, extreme, or lack of affinity for the inactivated AChE. Ultimately oxime binding is necessary for AChE reactivation in a manner that is not well understood. We hypothesize that alternative oxime binding conformations within the AChE active site may contribute to the slow reactivation rates. To address the effects of alternative oxime binding conformations within AChE, we performed consensus molecular docking calculations of Hi6, 2PAM, Obidoxime, and MMB4 in four AChE target structures. Each structure differs from the others in the conformations of various residues in the entrance to and in the active site where interactions are made with the oxime compounds. The resulting docking poses are re-scored within a Generalized Born/Surface Area (GBSA)scoring function. We show that there is a significant proclivity for an alternate binding conformation of the oximes that lies between the adducted serine and Trp86 sidechain from the omega loop. This non-productive binding conformation is modulated by both the conformation of the adduct and by other residues in and near the protein active site.

Is alternative binding sapping the strength of current oxime countermeasures?

253rd National Meeting (2017)

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