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Identifying novel binders in MB327-PAM-1, an allosteric binding site crucial for treatment after organophosphorus poisoning

Affiliation
1Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Kaiser, Jesko;
Affiliation
Department of Pharmacy, Ludwig-Maximilians-Universität München, München, Germany
Nitsche, Valentin;
Affiliation
Department of Pharmacy, Ludwig-Maximilians-Universität München, München, Germany
Bernauer, Tamara;
Affiliation
1Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Gertzen, Christoph G.W.;
Affiliation
Department of Pharmacy, Ludwig-Maximilians-Universität München, München, Germany
Höfner, Georg;
Affiliation
Bundeswehr Institute of Pharmacology and Toxicology, München, Germany
Niessen, Karin V.;
Affiliation
Bundeswehr Institute of Pharmacology and Toxicology, München, Germany
Seeger, Thomas;
Affiliation
Bundeswehr Institute of Pharmacology and Toxicology, München, Germany
Thiermann, Horst;
Affiliation
Bundeswehr Institute of Pharmacology and Toxicology, München, Germany
Steinritz, Dirk;
Affiliation
Bundeswehr Institute of Pharmacology and Toxicology, München, Germany
Worek, Franz;
Affiliation
Department of Pharmacy, Ludwig-Maximilians-Universität München, München, Germany
Wanner, Klaus T.;
Affiliation
Department of Pharmacy, Ludwig-Maximilians-Universität München, München, Germany
Paintner, Franz F.;
Affiliation
1Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Gohlke, Holger

Organophosphorus compounds (OPCs) are highly toxic compounds that can block acetylcholinesterase, indirectly resulting in an overstimulation of nicotinic acetylcholine receptors (nAChRs). The current treatment after poisoning with OPCs to prevent toxic effects, such as respiratory paralysis, is insufficient. Thus, novel therapeutics are required to increase treatment efficacy. One is MB327, that has been found to reestablish neuromuscular transmission by interacting directly with nAChR, probably via allosteric mechanisms. Nevertheless, at higher concentrations MB327 acts as an inhibitor of nAChRs, counteracting its beneficial effects. Thus, novel resensitizers need to be developed.

In our work, we first identified a new potential allosteric binding pocket (MB327-PAM-1) of MB327 located at the transition of the extracellular to the transmembrane region using blind docking experiments and molecular dynamics simulations. The interacting amino acids are highly conserved among different subunits and different species of nAChR, corresponding to the fact that MB327 can interact with several subtypes of nAChR of different species. We also show that MB327 can have an allosteric effect on the orthosteric binding pocket and the transmembrane domain after binding to MB327-PAM-1. Based on this new knowledge, we performed high-throughput virtual screenings. Thereby, we identified four novel ligands binding to MB327-PAM-1 with increased affinity compared to MB327. Most interestingly, treatment of soman-poisoned rat diaphragm with one of these ligands, cycloguanil, in micromolecular concentrations led to the reestablishment of the muscle force.

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