Shah Falgun, Mukherjee Prasenjit, Desai Prashant, Avery Mitchell
Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
Curr Comput Aided Drug Des. 2010 Mar;6(1):1-23. doi: 10.2174/157340910790980142.
Cysteine proteases are implicated in a variety of human physiological processes and also form an essential component of the life cycle of a number of pathogenic protozoa and viruses. The present review highlights the drug design approaches utilized to understand the mechanism of inhibition and discovery of inhibitors against protozoal cysteine protease, falcipain (a cysteine protease of P. falciparum which causes malaria), and viral cysteine protease, SARS-CoV M(pro) (a cysteine protease of severe acute respiratory syndrome corona virus). The article describes rational approaches for the design of inhibitors and focuses on a variety of structure as well as ligand-based modeling strategies adopted for the discovery of the inhibitors. Also, the key features of ligand recognition against these targets are accentuated. Although no apparent similarities exist between viral and protozoal cysteine proteases discussed here, the goal is to provide examples of rational drug design approaches adopted to design inhibitors against these proteases. The current review would be of interest to scientists engaged in the development of drug design strategies to target the cysteine proteases present in mammals and other lower order organisms.
半胱氨酸蛋白酶参与多种人类生理过程，也是许多致病原生动物和病毒生命周期的重要组成部分。本综述重点介绍了用于理解抑制机制以及发现针对原生动物半胱氨酸蛋白酶（恶性疟原虫的半胱氨酸蛋白酶，即导致疟疾的疟原虫蛋白酶）和病毒半胱氨酸蛋白酶（严重急性呼吸综合征冠状病毒的半胱氨酸蛋白酶SARS-CoV M(pro)）抑制剂的药物设计方法。本文描述了抑制剂设计的合理方法，并着重介绍了为发现抑制剂而采用的各种基于结构以及基于配体的建模策略。此外，还强调了针对这些靶点的配体识别的关键特征。尽管本文讨论的病毒和原生动物半胱氨酸蛋白酶之间没有明显的相似之处，但目的是提供合理药物设计方法的实例，这些方法用于设计针对这些蛋白酶的抑制剂。本综述将对致力于开发针对哺乳动物和其他低等生物中存在的半胱氨酸蛋白酶的药物设计策略的科学家们有所帮助。
