Molecular modelling and crystallographic investigation of novel synthetic cathinone 2-methyl-4'-(methylthio)-2-morpholinopropiophenone (MMMP)

Abstract

2-Methyl-4'-(methylthio)-2-morpholinopropiophenone (MMMP) is a highly modified synthetic cathinone derived from natural occurring cathinone, the main psychoactive alkaloid present in Catha edulis Forsk. or khat. Synthetic cathinones (SCs) belong to the drug class of new psychoactive substances (NPS) which consists of analogues of commonly known abused drugs designed to mimic the psychoactive properties of illicit drugs to circumvent current drug legislations. From a structural perspective, cathinone is a β-keto analogue of amphetamine and SCs are often referred to as “bk-amphetamines”. SCs are capable of evoking psychoactive effects similar to that of amphetamines and cocaine increasing their popularity amongst users as “legal highs”. MMMP itself is commercially available and readily used in the polymer and printing industry in the fixing of thin films, plastics and inks as a Type 1 fragmenting photoinitiator. It was hypothesised that MMMP might have psychoactive properties due to its cathinone origin and isolation in confiscated drug samples. This hypothesis was investigated through molecular modelling techniques to determine if MMMP was capable of interacting with 25 protein targets consisting of 24 monoamine receptors and a transporter which act as common targets for psychoactive substances. From the initial molecular docking results two protein targets, serotonin-1A (SER1A) and serotonin transporter (SERT), were identified as the most likely to form a complex with MMMP. Further analysis through Molecular Dynamics (MD) simulations to evaluate the stability and movement of these complexes revealed that MMMP has a higher probability of interacting and forming a strong complex with the SERT binding pocket, but a weaker complex is formed with SER1A. The crystal structure of MMMP was successfully elucidated through single crystal X-ray diffraction (SCXRD). Analysis of the crystal structure revealed that MMMP crystallises in the non-centrosymmetric space group, Pca21. The unit cell consist of four crystallographically independent conformers with each conformer interacting with itself, with conformers within the same unit cell as well as with conformers in adjacent unit cells through a series of intra- and intermolecular interactions. Three symmetry elements, two glide planes and a screw axis, were also identified.