Theoretical study of molecular structure, reactivity, and molecular docking of almotriptan and its metabolite

Abstract

In this work, we performed a computational study of almotriptan, N,N-dimethyl-2-[5-((pyrrolidin-1-ylsulfonyl)methyl)-1H-indol-3-yl]ethanamine (denoted as Almo-I), and its metabolite, 4-(((3-(2-(dimethylamino)ethyl)-1H-indol-5-yl)methyl)sulfonamido)butanoic acid (denoted as Almo-II). Both species were examined at the X / DGDZVP level of theory (X = B3LYP, M06, M06L and ωB97XD). The reactive sites were identified through evaluation of the Fukui function using frozen-core and finite-difference approaches. For Almo-I, the sites most susceptible to nucleophilic attack are mainly located on the indole ring, whereas those prone to electrophilic attack are associated with the pyrrole double-bond region. The highest susceptibility toward radical attack was found at atoms C12, C13 and C14. In the case of Almo-II, the regions susceptible to nucleophilic attack shift from the indole ring toward the sulfonamide group, while the susceptibility to electrophilic and radical attack remains essentially unchanged. In addition, molecular docking studies showed favorable predicted interactions of Almo-I and Almo-II with the 5-HT1B receptor, with docking scores of −38.07 and −33.47 kJ mol⁻¹, respectively. Almo-I interacted mainly with Tyr218 and Phe331 through hydrogen-bond, π–π, and van der Waals interactions, whereas Almo-II interacted with Arg236, Arg310, and Lys314 through hydrogen-bond and π-cation interactions. The more favorable docking score and binding orientation of Almo-I are consistent with its placement within the previously reported binding site. These findings contribute to a better understanding of the molecular and reactivity characteristics of almotriptan and its metabolite and may provide useful insights into its mechanism of action and drug–receptor recognition relevant to its therapeutic activity.