非磺胺碳酸酐酶抑制剂的结构进展:设计、生物活性和结合机制的见解。

IF 3.6 3区 医学 Q2 CHEMISTRY, MEDICINAL
Mahmood Ahmed, Muhammad Zaeem Mehdi, Mehwish Javed, Mohammed H. AL Mughram, Masooma Irfan, Ahmad Saeed, Ali Abbas Aslam
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引用次数: 0

摘要

碳酸酐酶(carbon anhydrases, CAs)是一组促进二氧化碳可逆催化水合作用的金属酶,在pH调节、呼吸和电解质分泌中起着至关重要的作用。特定CA亚型的失调,特别是人类变体hCA I、II、IX和XII,与多种病理状况有关,包括青光眼、癫痫、肥胖和各种癌症。传统上,磺胺类抑制剂在治疗领域占据主导地位;然而,它们的局限性,如脱靶副作用、对不同同种异构体的选择性差和过敏反应,激发了人们对替代支架的兴趣。这篇全面的综述严格审查了新兴的一类针对hCA异构体的非磺胺抑制剂,重点关注化学多样性、结合机制和最近开发的酚类、羧酸类、香豆素类、二硫代氨基甲酸酯类和多胺类的构效关系。特别注意到x射线晶体学和计算模型的进展,这些进展已经阐明了与经典磺胺相互作用不同的结合模式。通过对最新研究结果的综合,本文旨在指导今后合理设计选择性和有效的非磺胺类CA抑制剂用于临床应用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Structural Advances in Non-Sulfonamide Carbonic Anhydrase Inhibitors: Insights Into Design, Bioactivity, and Binding Mechanism

Structural Advances in Non-Sulfonamide Carbonic Anhydrase Inhibitors: Insights Into Design, Bioactivity, and Binding Mechanism

Carbonic anhydrases (CAs) belong to a set of metalloenzymes that facilitate the reversible catalytic hydration of CO2, playing crucial roles in pH regulation, respiration, and electrolyte secretion. Dysregulation of specific CA isoforms, particularly the human variants hCA I, II, IX, and XII, is implicated in multiple pathological conditions, including glaucoma, epilepsy, obesity, and various cancers. Traditionally, sulfonamide-based inhibitors have dominated the therapeutic landscape; however, their limitations, such as off-target side effects, poor selectivity for different isoforms, and allergic reactions, have galvanized interest in alternative scaffolds. This comprehensive review critically examines the burgeoning class of non-sulfonamide inhibitors targeting hCA isoforms, focusing on the chemical diversity, binding mechanisms, and structure–activity relationships of recently developed phenols, carboxylic acids, coumarins, dithiocarbamates, and polyamines. Special attention is given to the advances in X-ray crystallography and computational modeling that have illuminated binding modes distinct from classical sulfonamide interactions. By synthesizing the latest findings, this review aims to guide future efforts in the rational design of selective and efficacious non-sulfonamide CA inhibitors for clinical application.

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来源期刊
Archiv der Pharmazie
Archiv der Pharmazie 医学-化学综合
CiteScore
7.90
自引率
5.90%
发文量
176
审稿时长
3.0 months
期刊介绍: Archiv der Pharmazie - Chemistry in Life Sciences is an international journal devoted to research and development in all fields of pharmaceutical and medicinal chemistry. Emphasis is put on papers combining synthetic organic chemistry, structural biology, molecular modelling, bioorganic chemistry, natural products chemistry, biochemistry or analytical methods with pharmaceutical or medicinal aspects such as biological activity. The focus of this journal is put on original research papers, but other scientifically valuable contributions (e.g. reviews, minireviews, highlights, symposia contributions, discussions, and essays) are also welcome.
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