Shunmugam Letitia, Ramharack Pritika, Soliman Mahmoud E S
Molecular Modeling and Drug Design Research Group, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.
College of Pharmacy and Pharmaceutical Sciences, Florida Agricultural and Mechanical University, FAMU, Tallahassee, FL, 32307, USA.
Protein J. 2017 Oct;36(5):397-406. doi: 10.1007/s10930-017-9736-8.
Over the last 2 decades, covalent inhibitors have gained much popularity and is living up to its reputation as a powerful tool in drug discovery. Covalent inhibitors possess many significant advantages including increased biochemical efficiency, prolonged duration and the ability to target shallow, solvent exposed substrate-binding domains. However, rapidly mounting concerns over the potential toxicity, highly reactive nature and general lack of selectivity have negatively impacted covalent inhibitor development. Recently, a great deal of emphasis by the pharmaceutical industry has been placed toward the development of novel approaches to alleviate the major challenges experienced through covalent inhibition. This has unexpectedly led to the emergence of "selective" covalent inhibitors. The purpose of this review is not only to provide an overview from literature but to introduce a technical guidance as to how to initiate a systematic "road map" for the design of selective covalent inhibitors which we believe may assist in the design and development of optimized potential selective covalent HCV NS3/4A viral protease inhibitors.
在过去的20年里，共价抑制剂越来越受欢迎，并且不负其作为药物发现中强大工具的声誉。共价抑制剂具有许多显著优势，包括提高生化效率、延长作用时间以及能够靶向暴露于溶剂中的浅底物结合结构域。然而，对潜在毒性、高反应活性以及普遍缺乏选择性的担忧迅速增加，对共价抑制剂的开发产生了负面影响。最近，制药行业高度重视开发新方法，以缓解共价抑制所面临的主要挑战。这意外地导致了“选择性”共价抑制剂的出现。本综述的目的不仅是对文献进行概述，还将介绍一份技术指南，说明如何启动一个系统的“路线图”来设计选择性共价抑制剂，我们相信这可能有助于设计和开发优化的潜在选择性共价丙肝病毒NS3/4A病毒蛋白酶抑制剂。
