Computational identification of human targets of mitragynine – the main active compound of Mitragyna speciosa

Abstract

Even though several studies have been conducted in attempts to find the potential medical applications of kratom (Mitragyna speciosa) extracts, the molecular understanding of its main active substance, mitragynine, remains to be further elucidated. In this study, we used bioinformatic approaches to identify putative protein targets of mitragynine and their binding associations. Human targets of mitragynine were identified using 2 methods: protein and drug similarity approaches. First, 155 homologous proteins of delta-opioid receptor were obtained through a BLASTP search. Second, 12 drugs similar to mitragynine were identified, many of which are used for treating hypertension and cognitive and psychotic disorders. From both approaches, the protein targets with available 3D structures were verified using docking simulations. Out of 48 candidates (39 from BLASTP search and 9 from drug similarity approach), 10 are known in the literature while the rest require further in vitro investigation. Examples of these targets are orexin/hypocretin receptor type 1, 5-hydroxytryptamine receptor 1B, and orexin receptor type 2, which had very strong predicted binding affinity of −9.3, −9.2, and −9.0 kcal/mol, respectively. Moreover, docking simulations suggest that mitragynine may replace commercial drugs in most of the receptor binding pockets, highlighting its potential application in drug repositioning. This in silico study provides insights into the molecular mechanism of mitragynine, which can help inform clinical researchers in developing safe and effective medical applications of kratom.