1. Academic Validation
  2. Halogen bonding for the design of inhibitors by targeting the S1 pocket of serine proteases

Halogen bonding for the design of inhibitors by targeting the S1 pocket of serine proteases

  • RSC Adv. 2018 Aug 6;8(49):28189-28197. doi: 10.1039/c8ra03145b.
Longguang Jiang 1 Xu Zhang 2 Yang Zhou 1 Yayu Chen 1 Zhipu Luo 3 Jinyu Li 1 Cai Yuan 4 Mingdong Huang 1
Affiliations

Affiliations

  • 1 College of Chemistry, Fuzhou University Fuzhou 350116 China jianglg@fzu.edu.cn HMD_lab@fzu.edu.cn.
  • 2 Center for Life Science, School of Life Sciences, Yunnan University Kunming 650021 China.
  • 3 Synchrotron Radiation Research Section, NCI, Argonne National Laboratory Argonne Illinois 60439 USA.
  • 4 College of Biological Science and Engineering, Fuzhou University Fuzhou 350116 China.
Abstract

Halogen bonding (or X bonding) has attracted increasing interest due to its significant role in molecular recognition in biological systems. Trypsin-like serine proteases have many physiological and pathophysiological functions. There is therefore extensive interest in generating specific inhibitors for pharmacological intervention in their enzymatic activity. We study here if it is possible to use halogenated compounds as the P1 group to bind to the S1 specificity pocket of trypsin-like serine proteases to avoid the low bioavailability of the amidine or guanidine P1 group that is typically used in many inhibitors. We used 4-chlorobenzylamine (ClBA), 4-bromobenzylamine (BrBA) and 4-iodobenzylamine (IBA) as probes to test their binding modes to a trypsin-like serine protease, urokinase-type plasminogen activator (uPA), which has been recognized as a marker for breast Cancer and an important target for inhibitor development. The results showed that these compounds inhibited uPA with stronger efficacies compared with their non-halogenated analogues. We also determined the high-resolution crystal structures of uPA in complex with BrBA and IBA, respectively. The structures revealed that BrBA bound to the S1 pocket of uPA via halogen bonds, but IBA did not make halogen bonds with uPA, demonstrating that the iodine may not be the best choice as a target moiety for serine proteases. These results advocate halogen bonding, especially bromine bonding, as an efficient strategy for the future design of novel inhibitors against trypsin-like serine proteases to provide strong potency and promote bioavailability.

Figures
Products
我们的 Cookie 政策

我们使用 Cookies 和类似技术以提高网站的性能和提升您的浏览体验,部分功能也使用 Cookies 帮助我们更好地理解您的需求,为您提供相关的服务。 如果您有任何关于我们如何处理您个人信息的疑问,请阅读我们的《隐私声明》