抽象的

A Modeling Approach towards Identifying Potential Bivalent Sensitizers of Neuromuscular Blocking Agents

Marc Pudlo, Lucie Javot, Paul Michel Mertes, Philippe Trechot, Pierre Gillet and Nadine Petitpain

Objective: Anaphylactic reactions induced by neuromuscular blocking agents (NMBAs) can occur at first contact and might be due to cross-sensitization by other drugs or chemicals. Our aim was to investigate whether divalent molecules sharing chemical features with NMBAs might potentially cause cross-sensitization. Methods: We constructed a pharmacophore key from chemical features common to all NMBAs (two positive or ionizable features 1.0807 nm apart) and used the key to screen FDA-approved small drug molecules of the Drug Bank® database (1541 molecules). The selected molecules were categorized on the basis of the values for three main parameters (fit value, relative energy and mean polar surface area). Results: Screening from the pharmacophore key selected 13 NMBAs and 88 non-NMBA drugs. Of these 88 drugs, 42 had high-ranking parameter values and were considered preferential cross-sensitizers. These included the dopamine D2 receptor ligands aripiprazole and domperidone. Pholcodine, as well as nizatidine, ranitidine, antrafenine, cabergoline and, to some extent, chlorhexidine best fulfilled the required criteria of apolar character, bioavailability and ionization rate. Conclusion: Our data support the hypothesis that pholcodine might be a potential NMBA cross-sensitizer. They confirmed the results of inhibition tests on patient serum suggesting that dopamine D2 receptor ligands might be cross-sensitizers. They also identified chlorhexidine, a widely used disinfectant incriminated in several cases of immediate hypersensitivity reactions, as a potential cross-sensitizer. Pharmacophore modelling is an inexpensive, straightforward approach that can be used to identify potential NMBA cross-sensitizing agents.