当前位置： SCI文献检索 > EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > In silico design of novel 2H-chromen-2-one derivatives as potent and selective MAO-B inhibitors.

In silico design of novel 2H-chromen-2-one derivatives as potent and selective MAO-B inhibitors.

Abstract：

:Inhibition data on rat monoamine oxidase B isoform of a large number of 7-metahalobenzyloxy-2H-chromen-2-one derivatives (67 compounds) carrying at position 4 a variety of substituents differing in steric, electrostatic, lipophilic and H-bonding properties, were modeled by Gaussian field-based 3D-QSAR and docking simulations carried out on rat MAO-B homology model. The computational study combining two different approaches provided easily interpretable binding modes, highlighting the dominant role of the steric effects at position 4, and guided the design of new, potent and selective MAO-B inhibitors. The 4-hydroxyethyl-, 4-chloroethyl-, 4-carboxamidoethyl-coumarin derivatives 70, 71, and 76, respectively, were endowed with high MAO-B inhibitory potency (pIC50 = 8.13, 7.89 and 7.82, respectively) and good selectivity over MAO-A (pIC50 = 5.33, 3% inhibition at 10 μM, and pIC50 = 5.37, respectively). New compounds with moderate to low MAO-B inhibitory activity were also designed and prepared to challenge the predictive power of our docking-based 3D-QSAR model. The good match between predicted and experimental pIC50 values for all the newly designed compounds confirmed the robustness of our model (r(2) = 0.856, RMSE = 0.421) and its transparent rationale in unveiling the main molecular determinants for high potency towards MAO-B.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Pisani L,Farina R,Nicolotti O,Gadaleta D,Soto-Otero R,Catto M,Di Braccio M,Mendez-Alvarez E,Carotti A

doi

10.1016/j.ejmech.2014.10.029

subject

Has Abstract

pub_date

2015-01-07 00:00:00

pages

98-105

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(14)00956-8

journal_volume

89

pub_type

杂志文章

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