Virtual Screening and Molecular Docking for Arylalkylamine-N-Acetyltransferase (aaNAT) Inhibitors, a Key Enzyme of &amp;lt;i&amp;gt;Aedes&amp;lt;/i&amp;gt; (Stegomyia) &amp;lt;i&amp;gt;aegypti&amp;lt;/i&amp;gt; (L.) Metabolism

Lourenço, Bruno Luis Alves; Silva, Maicon Vinícius Araújo Santos; Oliveira, Elisson Barros de; Soares, Wagner Rodrigues de Assis; Goés-Neto, Aristóteles; Santos, Gesivaldo; Andrade, Bruno Silva

doi:10.4236/cmb.2015.53005

Cited by 6 publications

(4 citation statements)

References 36 publications

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“…In this study, we have successfully cloned, expressed, purified, and characterized Bm -iAANAT, an arylalkylamine N -acyltransferase from Bombyx mori . The characterization of Bm -iAANAT contributes to the body of knowledge leading to a pest-specific iAANAT inhibitor, important because iAANATs are suggested as new targets for the development of insecticides [43–46]. The most important finding from our work was that Bm -iAANAT will accept long-chain acyl-CoA thioesters as substrates.…”

Section: Discussionmentioning

confidence: 80%

Bm -iAANAT and its potential role in fatty acid amide biosynthesis in Bombyx mori

Anderson

Battistini

Wallis

et al. 2018

Prostaglandins, Leukotrienes and Essential Fatty Acids

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The purpose of this research is to unravel the substrate specificity and kinetic properties of an insect arylalkylamine N-acyltransferase from Bombyx mori (Bm-iAANAT) and to determine if this enzyme will catalyze the formation of long chain N-acylarylalkylamides in vitro. However, the determination of substrates and products for Bm-iAANAT in vitro is no guarantee that these same molecules are substrates and products for the enzyme in the organism. Therefore, RT-PCR was performed to detect the Bm-iAANAT transcripts and liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QToF-MS) analysis was performed on purified lipid extracts from B. mori larvae (fourth instar, Bmi4) to determine if long chain fatty acid amides are produced in B. mori. Ultimately, we found that recombinant Bm-iAANAT will utilize long-chain acyl-CoA thioesters as substrates and identified Bm-iAANAT transcripts and long-chain fatty acid amides in Bmi4. Together, these data show Bm-iAANAT will catalyze the formation of long-chain N-acylarylalkylamides in vitro and provide evidence demonstrating that Bm-iAANAT has a role in fatty acid amide biosynthesis in B. mori, as well.

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Section: Discussionmentioning

confidence: 80%

Bm -iAANAT and its potential role in fatty acid amide biosynthesis in Bombyx mori

Anderson

Battistini

Wallis

et al. 2018

Prostaglandins, Leukotrienes and Essential Fatty Acids

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“…Inactivation of agmatine neurotransmission by N -acetylation is an underappreciated reaction between arginine, agmatine, and human disease 27 , 66 – 68 , the search for a human ortholog of Drosophila AgmNAT could lead to a new target for drug development. Additionally, selective targeting of Drosophila AgmNAT could result in the development of novel insecticides for insect control 20 – 23 .…”

Section: Resultsmentioning

confidence: 99%

“…A thorough study of the insect AANATs contributes to our understanding of fatty acid amide biosynthesis, enables a detailed comparison between the insect AANATs to the AANATs from other organisms, and fosters the development of insecticides targeted against insect AANATs. AANATs are suggested to be a good targets for the control of insect pests 20 – 23 . Furthermore, AANAT inhibitors could also lead to drugs to treat circadian rhythm disorders because serotonin N -acetyltransferase catalyzes the rate-determining step in melatonin biosynthesis 24 .…”

Section: Introductionmentioning

confidence: 99%

Structural and Mechanistic Analysis of Drosophila melanogaster Agmatine N-Acetyltransferase, an Enzyme that Catalyzes the Formation of N-Acetylagmatine

Dempsey

Nichols

Battistini

et al. 2017

Sci Rep

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Agmatine N-acetyltransferase (AgmNAT) catalyzes the formation of N-acetylagmatine from acetyl-CoA and agmatine. Herein, we provide evidence that Drosophila melanogaster AgmNAT (CG15766) catalyzes the formation of N-acetylagmatine using an ordered sequential mechanism; acetyl-CoA binds prior to agmatine to generate an AgmNAT•acetyl-CoA•agmatine ternary complex prior to catalysis. Additionally, we solved a crystal structure for the apo form of AgmNAT with an atomic resolution of 2.3 Å, which points towards specific amino acids that may function in catalysis or active site formation. Using the crystal structure, primary sequence alignment, pH-activity profiles, and site-directed mutagenesis, we evaluated a series of active site amino acids in order to assign their functional roles in AgmNAT. More specifically, pH-activity profiles identified at least one catalytically important, ionizable group with an apparent pKa of ~7.5, which corresponds to the general base in catalysis, Glu-34. Moreover, these data led to a proposed chemical mechanism, which is consistent with the structure and our biochemical analysis of AgmNAT.

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“…In situ reaction of the latter with an equal amount of 3-ethylaniline (4) produced acyl thioureas ( 5a – j ). The reaction of ethyl 4-ethoxypent-4-en-2-ynoate with ( 5a – j ) in dry ethanol at room temperature produced the required compounds ( 6a – j ) with outstanding yields and high purity [ 26 ]. The 2D structures of novel imino-thiazolidinone derivatives are shown in ( Figure 2 ).…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, Kinetic Analysis and Pharmacophore-Directed Discovery of 3-Ethylaniline Hybrid Imino-Thiazolidinone as Potential Inhibitor of Carbonic Anhydrase II: An Emerging Biological Target for Treatment of Cancer

et al. 2022

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Carbonic anhydrases (CA), having Zn2+ metal atoms, are responsible for the catalysis of CO2 and water to bicarbonate and protons. Any abnormality in the functioning of these enzymes may lead to morbidities such as glaucoma and different types of cancers including brain, renal and pancreatic carcinomas. To cope with the lack of presence of a promising therapeutic agent against these cancers, searching for an efficient and suitable carbonic anhydrase inhibitor is crucial. In the current study, ten novel 3-ethylaniline hybrid imino-thiazolidinones were synthesized and characterized by FTIR, NMR (1H, 13C), and mass spectrometry. Synthesis was carried out by diethyl but-2-ynedioate cyclization and different acyl thiourea substitutions of 3-ethyl amine. The CA (II) enzyme inhibition profile for all synthesized derivatives was determined. It was observed that compound 6e demonstrated highest inhibition of CA-II with an IC50 value of 1.545 ± 0.016 µM. In order to explore the pharmacophoric properties and develop structure activity relationship, in silico screening was performed. In silico investigations included density functional theory (DFT) studies, pharmacophore-guided model development, molecular docking, molecular dynamic (MD) simulations, and prediction of drug likeness scores. DFT investigations provided insight into the electronic characteristics of compounds, while molecular docking determined the binding orientation of derivatives within the CA-II active site. Compounds 6a, 6e, and 6g had a reactive profile and generated stable protein-ligand interactions with respective docking scores of −6.12, −6.99, and −6.76 kcal/mol. MD simulations were used to evaluate the stability of the top-ranked complex. In addition, pharmacophore-guided modeling demonstrated that compound 6e produced the best pharmacophore model (HHAAARR) compared to standard brinzolamide. In vitro and in silico investigations anticipated that compound 6e would be an inhibitor of carbonic anhydrase II with high efficacy. Compound 6e may serve as a potential lead for future synthesis that can be investigated at the molecular level, and additional in vivo studies are strongly encouraged.

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Virtual Screening and Molecular Docking for Arylalkylamine-N-Acetyltransferase (aaNAT) Inhibitors, a Key Enzyme of <i>Aedes</i> (Stegomyia) <i>aegypti</i> (L.) Metabolism

Cited by 6 publications

References 36 publications

Bm -iAANAT and its potential role in fatty acid amide biosynthesis in Bombyx mori

Bm -iAANAT and its potential role in fatty acid amide biosynthesis in Bombyx mori

Structural and Mechanistic Analysis of Drosophila melanogaster Agmatine N-Acetyltransferase, an Enzyme that Catalyzes the Formation of N-Acetylagmatine

Design, Synthesis, Kinetic Analysis and Pharmacophore-Directed Discovery of 3-Ethylaniline Hybrid Imino-Thiazolidinone as Potential Inhibitor of Carbonic Anhydrase II: An Emerging Biological Target for Treatment of Cancer

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