Discovery of Sulfanilamide-diazo Derivatives Incorporating Benzoic Acid Moieties as Novel Inhibitors of Human Carbonic Anhydrase II Activity.

IF 1.9 4区 生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
Farshid Belani, Maryam Mehrabi, Hadi Adibi, Masomeh Mehrabi, Reza Khodarahmi
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引用次数: 0

Abstract

Background: Sulfonamides are widely used carbonic anhydrase inhibitors (CAIs) in clinical settings, however, their nonspecific inhibition of multiple carbonic anhydrase isoforms can lead to reduced efficacy and side effects. This study aimed to develop sulfanilamide-diazo derivatives incorporating benzoic acid moieties as novel inhibitors of hCA II activity to reduce side effects and enhance selectivity for different CA isozymes.

Methods: We investigated the interaction between these derivatives and the hCA II isozyme via various spectroscopic and docking methods.

Results: The kinetic data demonstrates that compound 1 (C1) and compound 2 (C2) share a similar inhibitory strength against hCA II, effectively inhibiting its esterase activity through a noncompetitive mechanism with Ki values at low micromolar levels. Fluorescence measurements indicated that the synthesized compounds suppressed the inherent fluorescence of hCA II via a static quenching process, with each compound showing a singular binding site within the enzyme. Thermodynamic evidences highlight the significance of van der Waals interactions and hydrogen bonding in the binding process. The results of molecular docking indicated that both C1 and C2 effectively obstruct the entrance to hCA II's active site, with no significant differences in their binding conformations.

Conclusion: While C1 and C2 exhibit CA inhibitory potency lower than that of sulfonamide compounds, this study offers valuable insights that could pave the way for the development of a promising scaffold for designing new carbonic anhydrase inhibitors.

含有苯甲酸基团的磺胺类重氮衍生物作为人类碳酸酐酶II活性的新抑制剂的发现。
背景:磺胺类药物是临床上广泛使用的碳酸酐酶抑制剂(CAIs),然而,它们对多种碳酸酐酶异构体的非特异性抑制可能导致疗效降低和副作用。本研究旨在开发含有苯甲酸基团的磺胺类重氮衍生物作为hCA II活性的新型抑制剂,以减少副作用并提高对不同CA同工酶的选择性。方法:通过各种光谱和对接方法研究这些衍生物与hCA II同工酶的相互作用。结果:动力学数据表明,化合物1 (C1)和化合物2 (C2)对hCA II具有相似的抑制强度,通过低微摩尔Ki值的非竞争机制有效抑制其酯酶活性。荧光测量表明,合成的化合物通过静态猝灭过程抑制了hCA II的固有荧光,每个化合物在酶内显示一个单一的结合位点。热力学证据强调了范德华相互作用和氢键在结合过程中的重要性。分子对接结果表明,C1和C2均能有效阻断hCA II活性位点的入口,其结合构象无显著差异。结论:虽然C1和C2表现出比磺胺类化合物更低的CA抑制效力,但该研究提供了有价值的见解,可以为设计新的碳酸酐酶抑制剂的有前途的支架的开发铺平道路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Current protein & peptide science
Current protein & peptide science 生物-生化与分子生物学
CiteScore
5.20
自引率
0.00%
发文量
73
审稿时长
6 months
期刊介绍: Current Protein & Peptide Science publishes full-length/mini review articles on specific aspects involving proteins, peptides, and interactions between the enzymes, the binding interactions of hormones and their receptors; the properties of transcription factors and other molecules that regulate gene expression; the reactions leading to the immune response; the process of signal transduction; the structure and function of proteins involved in the cytoskeleton and molecular motors; the properties of membrane channels and transporters; and the generation and storage of metabolic energy. In addition, reviews of experimental studies of protein folding and design are given special emphasis. Manuscripts submitted to Current Protein and Peptide Science should cover a field by discussing research from the leading laboratories in a field and should pose questions for future studies. Original papers, research articles and letter articles/short communications are not considered for publication in Current Protein & Peptide Science.
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