In silico and in vitro pharmacological investigations of a natural alkaloid

TitleIn silico and in vitro pharmacological investigations of a natural alkaloid
Publication TypeJournal Article
Year of Publication2012
AuthorsAhmed AAE, Marki A, Gaspar R, Vasas A, Mudawi M, Jojart B, Minorics R, Hohmann J, Falkay G
JournalMedicinal Chemistry Research
Type of ArticleArticle

Abstract: Haplopine-3,3′-dimethylallyl ether (HAP) was isolated from a Sudanese herb (El-hazha), characterized and tested on isolated rat uterus rings pre-contracted with KCl by means of in vitro and in silico docking studies on a customized rat β2-adrenoceptor (β2-AR). The in vitro results revealed that HAP produces uterus-relaxant effects similar to those of terbutaline. Its Emax (the maximum relaxing effect against KCl-induced contraction) was approximately 80% that of terbutaline, whilst its EC50 (The concentration producing 50% of Emax) was ten times lower than that for terbutaline, showing greater potency and less efficacy. ICI-118,551 (a selective β2-AR antagonist) exhibited similar antagonism as concerns the relaxing effects of HAP and terbutaline, with p D2′ = 6.3 ± 0.2 and p A2 = 6.7 ± 0.2, respectively. The in silico results of β2-AR showed that HAP behaves similarly terbutaline except in the orientation within the active pocket. However, HAP has unique basic bond (His93) instead of the acidic bond at the most important site (Asp113) of β2-AR. This study suggests that the affinity is closely related to the interactions of the oxygen groups, whilst the difference in efficacy may be due to the lack of the Asp113 interaction. The correlation of the calculated ligand efficiency and Emax revealed that there was a direct strong relation between the efficiency and in vitro efficacy. Finally, it was concluded that HAP can be categorized as a β2-AR agonist; further pharmacokinetic and toxicological studies are required to complete its profile. Graphical Abstract: Left, Illustration of the lowest energy conformation of HAP (green) and the standard terbutaline (orange) docked into the active site of a customized rat β2-adrenoceptor, whilst right figure demonstrate dose-response curves of the relaxing activity of HAP (dashed line) and terbutaline (continuous line) on non-pregnant rat uterus in vitro against KCl-induced control contractions.