Evaluation of Selective COX-2 Inhibition and In Silico Study of Kuwanon Derivatives Isolated from.
Int J Mol Sci. 2021 Apr 1 ;22(7). Epub 2021 Apr 1. PMID: 33915826
Six kuwanon derivatives (A/B/C/E/H/J) extracted from the roots ofL. were evaluated to determine their cyclooxygenase (COX)-1 and 2 inhibitory effects. Cyclooxygenase (COX) is known as the target enzyme of nonsteroidal anti-inflammatory drugs (NSAIDs), which are the most widely used therapeutic agents for pain and inflammation. Among six kuwanon derivatives, kuwanon A showed selective COX-2 inhibitory activity, almost equivalent to that of celecoxib, a known COX inhibitor. Kuwanon A showed high COX-2 inhibitory activity (IC= 14μM) and a selectivity index (SI) range of>7.1, comparable to celecoxib (SI>6.3). To understand the mechanisms underlying this effect, we performed docking simulations, fragment molecular orbital (FMO) calculations, and pair interaction energy decomposition analysis (PIEDA) at the quantum-mechanical level. As a result, kuwanon A had the strongest interaction with Arg120 and Tyr355 at the gate of the COX active site (-7.044 kcal/mol) and with Val89 in the membrane-binding domain (-6.599 kcal/mol). In addition, kuwanon A closely bound to Val89, His90, and Ser119, which are residues at the entrance and exit routes of the COX active site (4.329Å). FMO calculations and PIEDA well supported the COX-2 selective inhibitory action of kuwanon A. It showed that the simulation and modeling results and experimental evidence were consistent.