A computer-assisted discovery of novel potential anti-obesity compounds as selective carbonic anhydrase VA inhibitors

Costa Giosue; Carta Fabrizio; Ambrosio Francesca Alessandra; Artese Anna; Ortuso Francesco; Moraca Federica; Rocca Roberta; Romeo Isabella; Lupia Antonio; Maruca Annalisa; Bagetta Donatella; Catalano Raffaella; Vullo Daniela; Alcaro Stefano; Supuran Claudiu T.

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A computer-assisted discovery of novel potential anti-obesity compounds as selective carbonic anhydrase VA inhibitors

机译：作为选择性碳酸酐酶VA抑制剂的计算机辅助发现新型潜在的抗肥胖化合物

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The human Carbonic anhydrases (hCA) VA and VB play a key role in ureagenesis, gluconeogenesis, lipogenesis and in the metabolism regulation, thus representing highly popular drug targets. Albeit several hCA inhibitors have been designed and are currently in clinical use, serious drug interactions have been reported due to their poor selectivity. In this perspective, the drug repurposing approach could be a useful tool in order to investigate the drug promiscuity/polypharmacology profile. In this study, virtual screening techniques and in vitro assays were combined to identify novel selective hCA VA inhibitors from among around 94000 compounds. The docking analysis highlighted 12 promising best hits, biologically characterized in terms of their hCA VA inhibitory activity. Interestingly, among them, the anticancer agents fludarabine and lenvatinib and the antiepileptic rufinamide were able to selectively inhibit the enzyme activity in the micromolar range, while a pyrido-indole derivative, the homovanillic acid sulfate and the desacetyl metabolite of the antibacterial cephapirin in the nanomolar range. (C) 2019 Elsevier Masson SAS. All rights reserved.

机译：人类碳酸酐酶（HCA）VA和VB中的尿素生成，糖异生，脂肪生成和在代谢调控中发挥关键作用，从而代表了广受欢迎的药物靶标。虽然几个HCA抑制剂的设计和目前在临床上使用，严重的药物相互作用进行了报道，由于其选择性差。从这个角度来看，药品再利用的做法可能是为了研究药物滥交/ polypharmacology轮廓的有用工具。在这项研究中，虚拟筛选技术和体外测定法组合以从大约94000的化合物中鉴定新的选择性HCA VA抑制剂。对接分析突出12个有为最佳匹配结果，生物特征的HCA VA抑制活性方面出发。有趣的是，其中，所述抗癌剂氟达拉滨和lenvatinib和抗癫痫卢非酰胺能够选择性地抑制在微摩尔范围内的酶活性，而吡啶并吲哚衍生物中，高香草酸硫酸盐和抗菌头孢匹林的在纳摩尔的去乙酰基代谢物范围。（c）2019年Elsevier Masson SAS。版权所有。

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来源
《European Journal of Medicinal Chemistry: Chimie Therapeutique》 |2019年第2019期|共8页
作者
Costa Giosue; Carta Fabrizio; Ambrosio Francesca Alessandra; Artese Anna; Ortuso Francesco; Moraca Federica; Rocca Roberta; Romeo Isabella; Lupia Antonio; Maruca Annalisa; Bagetta Donatella; Catalano Raffaella; Vullo Daniela; Alcaro Stefano; Supuran Claudiu T.;
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作者单位

Magna Graecia Univ Catanzaro Dipartimento Sci Salute Campus S Venuta Viale Europa I-88100;

Univ Firenze Sez Sci Farmaceut Dipartimento NEUROFARBA Florence Italy;

Magna Graecia Univ Catanzaro Dipartimento Sci Salute Campus S Venuta Viale Europa I-88100;

Magna Graecia Univ Catanzaro Dipartimento Sci Salute Campus S Venuta Viale Europa I-88100;

Magna Graecia Univ Catanzaro Dipartimento Sci Salute Campus S Venuta Viale Europa I-88100;

Magna Graecia Univ Catanzaro Dipartimento Sci Salute Campus S Venuta Viale Europa I-88100;

Magna Graecia Univ Catanzaro Dipartimento Sci Salute Campus S Venuta Viale Europa I-88100;

Univ Calabria Dipartimento Chim &

Tecnol Chim Via Pietro Bucci I-87036 Cosenza Italy;

Magna Graecia Univ Catanzaro Dipartimento Sci Salute Campus S Venuta Viale Europa I-88100;

Magna Graecia Univ Catanzaro Dipartimento Sci Salute Campus S Venuta Viale Europa I-88100;

Magna Graecia Univ Catanzaro Dipartimento Sci Salute Campus S Venuta Viale Europa I-88100;

Magna Graecia Univ Catanzaro Dipartimento Sci Salute Campus S Venuta Viale Europa I-88100;

Univ Firenze Sez Sci Farmaceut Dipartimento NEUROFARBA Florence Italy;

Magna Graecia Univ Catanzaro Dipartimento Sci Salute Campus S Venuta Viale Europa I-88100;

Univ Firenze Sez Sci Farmaceut Dipartimento NEUROFARBA Florence Italy;

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原文格式 PDF
正文语种 eng
中图分类药学;
关键词
Carbonic anhydrase; Obesity; Virtual screening; Drug repurposing; Isoform-selective inhibitors;

机译：碳酸酐酶;肥胖;虚拟筛选;药物重估;同种型选择性抑制剂;

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专利

1. A computer-assisted discovery of novel potential anti-obesity compounds as selective carbonic anhydrase VA inhibitors [J] . Costa Giosue, Carta Fabrizio, Ambrosio Francesca Alessandra, European Journal of Medicinal Chemistry: Chimie Therapeutique . 2019,第期

机译：作为选择性碳酸酐酶VA抑制剂的计算机辅助发现新型潜在的抗肥胖化合物
2. Carbonic anhydrase inhibitors: 2-substituted-1,3,4-thiadiazole-5-sulfamides act as powerful and selective inhibitors of the mitochondrial isozymes VA and VB over the cytosolic and membrane-associated carbonic anhydrases I, II and IV. [J] . Smaine FZ, Pacchiano F, Rami M, Bioorganic and Medicinal Chemistry Letters . 2008,第24期

机译：碳酸酐酶抑制剂：2-取代的1,3,4-噻二唑-5-磺酰胺可作为线粒体同工酶VA和VB的强力和选择性抑制剂，作用于胞质和膜相关的碳酸酐酶I，II和IV。
3. Discovery of Hydrazinecarboxamide or Hydrazinecarbothioamide Bearing Small Molecules as Dual Inhibitor of Ras Protein and Carbonic Anhydrase Enzyme as Potential Anticancer Agent Using Validated Docking Study and In-silico ADMET Profile. [J] . Supriyo Saha Research Journal of Pharmaceutical, Biological and Chemical Sciences . 2014,第3期

机译：使用验证的对接研究和In-silico ADMET分布图发现带有小分子的Ras蛋白和碳酸酐酶作为潜在抗癌剂的双分子的肼基甲酰胺或肼基甲硫基酰胺。
4. Carbonic anhydrase inhibitory potential of Lagenaria siceraria and identification of its bioactive compounds-An LC-MS/MS approach [C] . Joydeb Chanda, Pulok K Mukherjee, Rajarshi Biswas, ASMS Conference on Mass Spectrometry and Allied Topics . 2016

机译：Lagenaria Siceraria的碳酸酐酶抑制潜力和其生物活性化合物的鉴定 - LC-MS / MS方法
5. Computer-Assisted Drug Discovery Part I: Design, Development, Validation and Application of FRESH, a Novel In-Silico High-throughput Screening Program Part II: Monocarbonyl Curcumin Analogues: Heterocyclic Pleiotropic Kinase Inhibitors that Mediate Anticancer Properties Part III: Development of 2nd Generation NAMFIS Software Program [D] . Shi, Qi 2014

机译：计算机辅助药物发现，第一部分：FRESH的设计，开发，验证和应用，一种新型的硅中高通量筛选程序第二部分：单羰基姜黄素类似物：介导抗癌特性的杂环多效性激酶抑制剂第三部分：第二代药物的开发NAMFIS软件程序
6. Discovery of New 11′-Biphenyl-4-sulfonamidesas Selective Subnanomolar Human Carbonic Anhydrase II Inhibitors [O] . Giuseppe La Regina, Michela Puxeddu, Marianna Nalli, 2020

机译：发现新的11-Biphenyl-4-磺酰胺作为选择性亚甲胺醇碳酸酐酶II抑制剂
7. Cover Picture: Discovery of New Potential Anti-Infective Compounds Based on Carbonic Anhydrase Inhibitors by Rational Target-Focused Repurposing Approaches (ChemMedChem 17/2016) [O] . Giannamaria Annunziato, Andrea Angeli, Francesca DAlba, 2016

机译：封面图片：通过合理的目标重组方法发现基于碳酸酐酶抑制剂的新潜在抗感染性化合物（ChemMedchem 17/2016）

A computer-assisted discovery of novel potential anti-obesity compounds as selective carbonic anhydrase VA inhibitors

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