The beginning of 2019 marks the most recent addition to the OPCW list of prohibited chemical weapons, the A-type nerve agent organophosphates (OPs), widely known Novichoks. Those exquisitely toxic poisons, reportedly most toxic substances created by man, have claimed their first victims in the West in 2018 in the UK. Ever since their creation in 1970-ies information on Novichok identity, chemical structure and precise mechanism of action remained unavailable and controversial. Most likely cause of their acute toxicity appears covalent inhibition of the enzyme acetylcholinesterase (AChE).<br/>We have used virtual reality (VR) atomic level macromolecular visualization (Nanome Inc, La Jolla) to analyze our 3D models of dozens of publicly available chemical structures reported as Novichok agents and selected several with steric and electronic features most likely representing the actual AChE inhibitors of the A-type: A-230, A-232 and A-234. Covalent conjugates with the active Ser203 of human AChE were then created in VR by bonding Novichok P atom to the Ser203 Oγ and subsequently allowing OP fragment to relax in VR using one of four available force fields. Clearly observed common significant steric complementarity between bound Novichoks and surrounding AChE geometry underlined usefulness of VR technology in the comparative analysis.<br/>Details of unique inhibitory Novichok stabilization not seen in other OP conjugates emerged, revealing likely molecular basis of their strong, resistant binding and high toxicity.

Computational modeling of Novichok interaction with acetylcholinesterase in VR

2019 Fall National Meeting

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