Abstract
Monoamine oxidases (MAOs) are attractive targets in drug design. The inhibition of one of the isoforms (A or B) is responsible for modulating the levels of different neurotransmitters in the central nervous system, as well as the production of reactive oxygen species. Molecules that act selectively on one of the MAO isoforms have been studied deeply, and coumarin has been described as a promising scaffold. In the current manuscript we describe a comparative study between 3-phenylcoumarin (endo coumarin-resveratrol-inspired hybrid) and trans-6-styrylcoumarin (exo coumarin-resveratrol-inspired hybrid). Crystallographic structures of both compounds were obtained and analyzed. 3D-QSAR models, in particular CoMFA and CoMSIA, docking simulations and molecular dynamics simulations have been performed to support and better understand the interaction of these molecules with both MAO isoforms. Both molecules proved to inhibit MAO-B, with trans-6-styrylcoumarin being 107 times more active than 3-phenylcoumarin, and 267 times more active than trans-resveratrol.
Highlights
Monoamine oxidases (MAOs) are very interesting and well-characterized targets in drug design and discovery [1]
The QSARand andtrans-6-styrylcoumarin, docking data together aim to shedtwo light on the interaccoumarin-resveratrol-inspired hybridization—endo and exo—are explored
The structures selected for this study present chemical similarity to the coumarin-resveratrol-inspired hybrids under study
Summary
Monoamine oxidases (MAOs) are very interesting and well-characterized targets in drug design and discovery [1]. Norepinephrine, epinephrine and melatonin are mostly degraded by MAO-A, phenethylamine and benzylamine are mostly degraded by MAO-B, and both isoforms mediate the degradation of dopamine, tryptamine and tyramine [1,2,3]. Selective MAO inhibitors have been extensively studied [3]. MAO-B selective compounds may be interesting in the search for new molecules against Parkinson diseases [4], whereas MAO-A inhibitors are selectively used in therapeutics for depression [5]. The design of compounds with selective activity on one of both
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