分子胶降解剂:新药发现的激动人心的机遇。

IF 6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Expert Opinion on Drug Discovery Pub Date : 2024-04-01 Epub Date: 2024-01-24 DOI:10.1080/17460441.2024.2306845
Thomas Lemaitre, Marie Cornu, Florian Schwalen, Marc Since, Charline Kieffer, Anne Sophie Voisin-Chiret
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引用次数: 0

摘要

导言:分子胶降解剂(MGDs)是一个概念,指的是一类能够促进细胞内两种蛋白质或分子之间相互作用的化合物。这些化合物可作为桥梁,增强特定的蛋白质-蛋白质相互作用(PPI)。在过去的十年中,这种技术作为一种潜在的策略受到了关注,可以靶向传统上被认为无法使用小分子药物的蛋白质:本综述介绍了细胞平衡的概念以及蛋白质合成与降解之间的平衡。蛋白质降解的概念涉及分子粘合剂,它是更广泛的靶向蛋白质降解(TPD)领域的一部分。接下来,通过基于配体的药物设计(LBDD)、基于结构的药物设计(SBDD)和基于片段的药物设计(FBDD)的实例,详细介绍了合理设计 MGDs 的药理化学策略:在开发治疗无法治愈或对传统疗法有抗药性的疾病的药物时,扩大有效靶向药物的范围将提供新的治疗选择。治疗微生物感染和神经退行性疾病是一项重大的社会挑战,而发现MGDs似乎是一个很有前景的途径。结合不同的方法来发现和利用各种创新治疗剂,将为治疗仍无法治愈的疾病创造机会。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Molecular glue degraders: exciting opportunities for novel drug discovery.

Introduction: Molecular Glue Degraders (MGDs) is a concept that refers to a class of compounds that facilitate the interaction between two proteins or molecules within a cell. These compounds act as bridge that enhances specific Protein-Protein Interactions (PPIs). Over the past decade, this technology has gained attention as a potential strategy to target proteins that were traditionally considered undruggable using small molecules.

Areas covered: This review presents the concept of cellular homeostasis and the balance between protein synthesis and protein degradation. The concept of protein degradation is concerned with molecular glues, which form part of the broader field of Targeted Protein Degradation (TPD). Next, pharmacochemical strategies for the rational design of MGDs are detailed and illustrated by examples of Ligand-Based (LBDD), Structure-Based (SBDD) and Fragment-Based Drug Design (FBDD).

Expert opinion: Expanding the scope of what can be effectively targeted in the development of treatments for diseases that are incurable or resistant to conventional therapies offers new therapeutic options. The treatment of microbial infections and neurodegenerative diseases is a major societal challenge, and the discovery of MGDs appears to be a promising avenue. Combining different approaches to discover and exploit a variety of innovative therapeutic agents will create opportunities to treat diseases that are still incurable.

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来源期刊
CiteScore
10.20
自引率
1.60%
发文量
78
审稿时长
6-12 weeks
期刊介绍: Expert Opinion on Drug Discovery (ISSN 1746-0441 [print], 1746-045X [electronic]) is a MEDLINE-indexed, peer-reviewed, international journal publishing review articles on novel technologies involved in the drug discovery process, leading to new leads and reduced attrition rates. Each article is structured to incorporate the author’s own expert opinion on the scope for future development. The Editors welcome: Reviews covering chemoinformatics; bioinformatics; assay development; novel screening technologies; in vitro/in vivo models; structure-based drug design; systems biology Drug Case Histories examining the steps involved in the preclinical and clinical development of a particular drug The audience consists of scientists and managers in the healthcare and pharmaceutical industry, academic pharmaceutical scientists and other closely related professionals looking to enhance the success of their drug candidates through optimisation at the preclinical level.
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