Deciphering the therapeutic role of Kigelia africana fruit in erectile dysfunction through metabolite profiling and molecular modelling. (2023)

• Record Type: Journal Article
• Authors: Olawale, Femi; Olofinsan, Kolawole; Ogunyemi, Oludare M.; Karigidi, Kayode O.; Gyebi, Gideon A.; Ibrahim, Ibrahim M.; Iwaloye, Opeyemi
• Is Part Of: Informatics in medicine unlocked. Volume 37(2023)
• Publication Date: 2023
• Subjects: Kigelia africana -- Erectile dysfunction -- Phytochemical analysis -- Molecular docking and dynamics -- QSAR; Medical informatics -- Periodicals; 610.285
• DOI: 10.1016/j.imu.2023.101190
• Languages: English
• ISSNs: 2352-9148

Abstract

Abstract: Kigelia africana herbal products are often used traditionally to treat erectile dysfunction and other sexual complaints, but the underlying mechanism is not yet understood. This study focused on profiling the bioactive constituents of Kigelia africana fruit (KAF) using spectroscopic techniques and providing the computational models of their interactions with phosphodiesterase (PDE5) and Rho-associated coiled-coil containing protein kinase 2 (ROCK2) targets associated with erectile dysfunction. Integrated FT-IR, HPLC-MS, and GC-MS analysis revealed 152 (C1–C152) KAF compounds with highly diverse functional groups and chemical properties. Molecular docking showed several hit compounds as potential inhibitors of PDE5 and ROCK2. Post docking MMGBSA, QSAR, predictive physicochemical analysis and AdmetSAR analysis revealed that most of the hit compounds are potential drug leads. Among these, hydroxydoxepin (C3) and ritodrine (C131) exhibited the strongest interactions with PDE5, while epigallocatechin 3- O -p-coumarate (C9) and chlorogenic acid (C91) had the strongest interaction with ROCK2. The thermodynamic parameters and trajectory clusters computed from the trajectories obtained from the 100 ns full atomistic molecular dynamic (MD) simulation indicated the structural stability and conformational flexibility of the selected complexes. The MD simulation-based MMPBSA calculation further revealed strong binding affinity and energy contribution by active site residues of PDE5 towards binding the selected KAF compounds. Various computational analyses employed revealed that the catalytic residues Gln817, Val782 and Phe786 of PDE5 exhibited high interaction potential and flexibility towards C3 and C131. Overall, hydroxydoxepin, ritodrine and other phytochemicals in Kigelia africana may account for the therapeutic role of this plant in erectile dysfunction. Graphical abstract: Image 1 Highlights: MetaBolite profiling of Kigelia africana, a medicinal plant traditionally used for erectile dysfunction, revealed 152 phytochemicals. In silico screening through molecular docking, post docking MMGBSA, QSAR and AdmetSAR revealed drug-like compounds against PDE5 and ROCK2. The phytocompounds had strong interactions with the catalytic residues of the target ezymes in erectile dysfunction. The molecular interactions were preserved in a dynamic environment during a 100 ns MD simulation as indicated by the thermodynamic parameters. Selected complexes showed high stability as indicated by cluster analysis and free energy simulation through dynamics-based MMPBSA computations.