Combined 3D-QSAR and docking analysis for the design and synthesis of chalcones as potent and selective monoamine oxidase B inhibitors

Mellado, Marco; González, César; Mella, Jaime; Aguilar, Luís Fuentes; Viña, Dolores; Uriarte, Eugenio; Cuéllar, Mauricio; Matos, María Joäo

doi:10.1016/j.bioorg.2021.104689

Cited by 29 publications

(22 citation statements)

References 34 publications

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“…The 3D-QSAR studies (CoMFA and CoMSIA models) were developed according to the procedure previously reported by our research group [ 8 ], using Sybyl X software (Tripos Inc., St. Louis, MO, USA). The data set used for the CoMFA and CoMSIA models were formed by 30 compounds presenting h MAO-A inhibitory activity and 157 compounds presenting h MAO-B inhibitory activity (6 selective MAO-A inhibitors, 133 selective MAO-B inhibitors and 24 non-selective MAO-A/MAO-B inhibitors), as previously published by our research group ( Supplementary Materials Figure S4 , Tables S7 and S8 ) [ 8 , 18 ]. To develop the models that relate the chemical structure and the inhibitory activity of differently substituted coumarins on MAO-A and MAO-B, an in-depth QSAR study of a wide variety of coumarins was carried out.…”

Section: Resultsmentioning

confidence: 99%

“…MAO-A (PDB ID = 2Z5Y) [ 37 ] and MAO-B (PDB ID = 1GOS) [ 38 ] crystal structures, and Autodock vina [ 39 ] software, were used in this study. PyMOL [ 40 ] and LigPlot + [ 41 , 42 ] were used to visualize the results, according to what had been reported by our research group [ 8 , 18 , 43 ]. The results for the MAO-A enzyme are not shown here; all the results are included in the supporting information ( Supplementary Materials Figure S8 ).…”

Section: Resultsmentioning

confidence: 99%

“…Computer-aided approaches have been widely used in this field [ 6 ]. The design of compounds with selective activity on one of both MAO isoforms has been supported by both quantitative structure–activity relationship (QSAR) and molecular docking techniques [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

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Coumarin-Resveratrol-Inspired Hybrids as Monoamine Oxidase B Inhibitors: 3-Phenylcoumarin versus trans-6-Styrylcoumarin

et al. 2022

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Coumarin-Resveratrol-Inspired Hybrids as Monoamine Oxidase B Inhibitors: 3-Phenylcoumarin versus trans-6-Styrylcoumarin

et al. 2022

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“…The study was performed according to the previous report of our research group. 18 − 22 Due to the scarce information on benzimidazole derivatives as aromatase inhibitors, we used the indole and benzofuran cores for the molecular alignment (all details are given in Table S1 ). All of the compounds span a biological activity range of more than 3 logarithmic units ( Figure S2 ).…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Molecular Modeling Studies of a Novel Benzimidazole as an Aromatase Inhibitor

et al. 2022

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In this study, a series of novel 1,3,4-oxadiazole-benzimidazole derivatives were designed and synthesized. Their cytotoxic activities against five cancer cell lines, including A549, MCF-7, C6, HepG2, and HeLa, were evaluated by the MTT assay. The compounds 5b , c showed satisfactory potencies with much higher anticancer activity in comparison to the reference drug doxorubicin against the studied cancer cell lines. In vitro , enzymatic inhibition assays of aromatase (ARO) enzymes were performed. Molecular docking, molecular dynamics simulations, and binding free energy analyses were used to better understand the structure–activity connections and mechanism of action of the aromatase inhibitors. Two types of satisfactory 3D-QSAR (CoMFA and CoMSIA) models were generated, to predict the inhibitory activities of the novel inhibitors. Molecular docking studies were also carried out to find their binding sites and types of their interactions with the aromatase enzyme. Additionally, molecular dynamics simulations were performed to explore the most likely binding modes of compounds 5b , c with CYP19A1.

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“…The presence of α,β-unsaturated ketone, carboxamide, multi-conjugated ketone, and olefinic linkage contribute to the versatility of the pharmacophore features of selective MAO-B inhibitors [ 19 , 20 , 21 , 22 , 23 , 24 ]. Recently, our group developed a new class of enamide-based MAO-B inhibitors by combining an olefinic linkage to the amide functional group.…”

Section: Introductionmentioning

confidence: 99%

Selected Class of Enamides Bearing Nitro Functionality as Dual-Acting with Highly Selective Monoamine Oxidase-B and BACE1 Inhibitors

Venkidath¹,

Dev³

et al. 2021

Molecules

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A small series of nitro group-bearing enamides was designed, synthesized (NEA1–NEA5), and evaluated for their inhibitory profiles of monoamine oxidases (MAOs) and β-site amyloid precursor protein cleaving enzyme 1 (β-secretase, BACE1). Compounds NEA3 and NEA1 exhibited a more potent MAO-B inhibition (IC50 value = 0.0092 and 0.016 µM, respectively) than the standards (IC50 value = 0.11 and 0.14 µM, respectively, for lazabemide and pargyline). Moreover, NEA3 and NEA1 showed greater selectivity index (SI) values toward MAO-B over MAO-A (SI of >1652.2 and >2500.0, respectively). The inhibition and kinetics studies suggested that NEA3 and NEA1 are reversible and competitive inhibitors with Ki values of 0.013 ± 0.005 and 0.0049 ± 0.0002 µM, respectively, for MAO-B. In addition, both NEA3 and NEA1 showed efficient BACE1 inhibitions with IC50 values of 8.02 ± 0.13 and 8.21 ± 0.03 µM better than the standard quercetin value (13.40 ± 0.04 µM). The parallel artificial membrane permeability assay (PAMPA) method demonstrated that all the synthesized derivatives can cross the blood–brain barrier (BBB) successfully. Docking analyses were performed by employing an induced-fit docking approach in the GLIDE module of Schrodinger, and the results were in agreement with their in vitro inhibitory activities. The present study resulted in the discovery of potent dual inhibitors toward MAO-B and BACE1, and these lead compounds can be fruitfully explored for the generation of newer, clinically active agents for the treatment of neurodegenerative disorders.

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Combined 3D-QSAR and docking analysis for the design and synthesis of chalcones as potent and selective monoamine oxidase B inhibitors

Cited by 29 publications

References 34 publications

Coumarin-Resveratrol-Inspired Hybrids as Monoamine Oxidase B Inhibitors: 3-Phenylcoumarin versus trans-6-Styrylcoumarin

Coumarin-Resveratrol-Inspired Hybrids as Monoamine Oxidase B Inhibitors: 3-Phenylcoumarin versus trans-6-Styrylcoumarin

Design, Synthesis, and Molecular Modeling Studies of a Novel Benzimidazole as an Aromatase Inhibitor

Selected Class of Enamides Bearing Nitro Functionality as Dual-Acting with Highly Selective Monoamine Oxidase-B and BACE1 Inhibitors

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