Exploring the Molecular Mechanisms of 17β-HSD5-induced Carcinogenicity of Catha Edulis via Molecular Modeling Approach.

Background The tradition of khat chewing has been deep-rooted in the African and Arabian Peninsula for centuries. Due to its amphetamine-like psycho-stimulant or euphoric effect, Khat has been used by millions in Somalia, Ethiopia, Saudi Arabia and Yemen. The long-term use of Khat can induce tremendous health outcomes, which may be serious and irreversible. Objective Prolong use of Khat constituents has been associated with different types of cancers such as prostatic, breast and ovarian cancer. However, it has been very difficult to identify the molecular targets involved in Khat carcinogenesis that interact with the Khat constituents by in vitro/in vivo experimental tools. Method In silico tools to predict potential targets involved in the carcinogenesis of Khat. Pass on-line prediction server was used for the prediction of a potential molecular target for Khat constituents. Molecular Dynamics simulation and MMGBSA calculation of the predicted target. Results Molecular Dynamics simulation and MM-GBSA calculation. Results revealed that among Khat constituents βSitosterol showed high binding affinity towards 17β-HSD5. On the other hand, this study highlights for the first time, some new interactions, which were observed in the case of cathine, cathinone and nerol during the simulation. Conclusion In silico molecular dynamic simulation tools were used for the first time to investigate the molecular mechanism of widely used leaves of psychoactive Khat (Catha edulis) constituent, which is used extensively all over the world. The present study provides deep insight to understand the effect of Khat constituents involve in the impairment of reproductive system and its binding to 17β-HSD5. ADMET profiling also suggested that few Khat constituents do not fulfill the requirements of Lipinski rule of five i.e. poor absorption and blood-brain barrier impermeability.