期刊
ACS CHEMICAL NEUROSCIENCE
卷 10, 期 8, 页码 3532-3542出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.9b00147
关键词
Irreversible inhibition; monoamine oxidase; hydride transfer; antiparkinsonian drugs; neurodegeneration; flavoenzymes
资金
- Croatian Science Foundation [IP-2014-09-3386]
Monoamine oxidases (MAOs) are flavin adenine dinucleotide containing flavoenzymes that catalyze the degradation of a range of brain neurotransmitters, whose imbalance is extensively linked with the pathology of various neurological disorders. This is why MAOs have been the central pharmacological targets in treating neurodegeneration for more than 60 years. Still, despite this practical importance, the precise chemical mechanisms underlying the irreversible inhibition of the MAO B isoform with clinical drugs rasagiline (RAS) and selegiline (SEL) remained unknown. Here we employed a combination of MD simulations, MM-GBSA binding free energy evaluations, and QM cluster calculations to show the MAO inactivation proceeds in three steps, where, in the rate-limiting first step, FAD utilizes its N5 atom to abstracts a hydride anion from the inhibitor alpha-CH2 group to ultimately give the final inhibitor-FAD adduct matching crystallographic data. The obtained free energy profiles reveal a lower activation energy for SEL by 1.2 kcal mol(-1) and a higher reaction exergonicity by 0.8 kcal mol(-1), with the former being in excellent agreement with experimental Delta Delta G(EXP)double dagger = 1.7 kcal mol(-1), thus rationalizing its higher in vivo reactivity over RAS. The calculated Delta G(BIND) energies confirm SEL binds better due to its bigger size and flexibility allowing it to optimize hydrophobic C-H center dot center dot center dot pi and pi-pi interactions with residues throughout both of enzyme's cavities, particularly with FAD, Gln206 and four active site tyrosines, thus overcoming a larger ability of RAS to form hydrogen bonds that only position it in less reactive orientations for the hydride abstraction. Offered results elucidate structural determinants affecting the affinity and rates of the inhibition reaction that should be considered to cooperate when designing more effective compounds devoid of untoward effects, which are of utmost significance and urgency with the growing prevalence of brain diseases.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据