双靶点抗肿瘤药物发现的支架跳跃策略：机遇与挑战
Scaffold hopping approaches for dual-target antitumor drug discovery: opportunities and challenges
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影响因子:4.9
分区:医学2区 / 药学2区
发表日期:2024 Nov
作者:
Anshul Mishra, Amandeep Thakur, Ram Sharma, Raphael Onuku, Charanjit Kaur, Jing Ping Liou, Sung-Po Hsu, Kunal Nepali
DOI:
10.1080/17460441.2024.2409674
摘要
支架跳跃已成为丰富小分子抗肿瘤剂合成库的实用策略，特别是它使化学家能够优化候选化合物的药效动力学、药代动力学和理化性质。支架跳跃开辟了超越已建立专利化学领域的新的分子空间。本文综述了基于支架跳跃的药物设计策略，用于双抑制性抗肿瘤结构模板的开发。通过微调结构、刚性化和简化（环闭合与开启）、以及彻底的结构改造，药物化学家生成了一系列双功能抑制剂。此外，本文还概述了支架跳跃的计算方法（软件和程序）以及用于合成通过支架跳跃设计的模板的有机钯催化技术。药物化学家在提供双重抑制性抗肿瘤结构方面展现了卓越的能力。基于支架跳跃的药物设计策略已产出大量药效优越的双重调控抗肿瘤剂。未来需要结合计算技术、合成方法创新与传统药物设计策略的整合，以增加支架跳跃辅助药物发现的项目数量。
Abstract
Scaffold hopping has emerged as a practical tactic to enrich the synthetic bank of small molecule antitumor agents. Specifically, it enables the chemist to refine the lead compound's pharmacodynamic, pharmacokinetic, and physiochemical properties. Scaffold hopping opens up fresh molecular territory beyond established patented chemical domains.The authors present the scaffold hopping-based drug design strategies for dual inhibitory antitumor structural templates in this review. Minor modifications, structure rigidification and simplification (ring-closing and opening), and complete structural overhauls were the strategies employed by the medicinal chemist to generate a library of bifunctional inhibitors. In addition, the review presents an overview of the computational methods of scaffold hopping (software and programs) and organopalladium catalysis leveraged for the synthesis of templates designed via scaffold hopping.The medicinal chemist has demonstrated remarkable prowess in furnishing dual inhibitory antitumor chemical architectures. Scaffold hopping-based drug design strategies have yielded a plethora of pharmacodynamically superior dual modulatory antitumor agents. An integrated approach involving computational advancements, synthetic methodology advancements, and conventional drug design strategies is required to increase the number of scaffold-hopping-assisted drug discovery campaigns.