Exploring novel indomethacin-derived compounds via investigation of NSAIDs through molecular docking and in vitro testing for anti-amyloid beta aggregation

Abstract

This study explores novel compounds derived from indomethacin, a nonsteroidal anti-inflammatory drug (NSAID), using several approaches. Molecular docking techniques were employed to assess the interaction potential of 35 NSAIDs with key molecular targets involved in amyloid beta (Aβ) aggregation, a critical process in Alzheimer's disease pathogenesis. Notably, amtolmetin guacil, indomethacin, lornoxicam, and meloxicam exhibited significant docking orientations with two key Aβ fragments, Aβ17-42 (2BEG) and AP25-35 (1QWP), which are crucial binding sites on the Aβ peptide. In vitro experiments evaluated the ability of six NSAIDs to inhibit Aβ aggregation through ThT flavin assays. Indomethacin emerged as the prototype molecule for developing a novel anti-aggregation agent targeting Aβ due to its strong binding affinities along with effective inhibitory activity. Subsequently, 13 designed compounds were examined for their binding affinities at 2BEG and 1QWP, using parameters similar to NSAIDs. Among them, B2 and B4 demonstrated notable binding affinities and interactions with critical residues indicating their potential as anti-Aβ aggregation agents. Molecular dynamic simulation studies confirmed the stability of these complexes. In silico analysis of CNS permeation indicated the capability of compounds in the B series, notably B3 and B4, to be across the BBB. These findings illuminate the potential of indomethacin-derived compounds as promising candidates for further development as therapeutics targeting Aβ aggregation in Alzheimer's disease. Moreover, these investigations are expected to aid in the design and creation of new small molecules possessing anti-Aβ aggregation properties.