N-磺酰基二肽腈作为人组织蛋白酶 S 的抑制剂：基于计算机的设计、合成和生化特性分析。

N-Sulfonyl dipeptide nitriles as inhibitors of human cathepsin S: In silico design, synthesis and biochemical characterization.

机构信息

Pharmaceutical Institute, Pharmaceutical and Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.

Pharmaceutical Institute, Pharmaceutical and Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany; Bonn Aachen International Center for Information Technology BIT, Life Science Informatics, University of Bonn, Endenicher Allee 19c, D-53115 Bonn, Germany; Instituto de Química de Sao Carlos, University of Sao Paulo, Avenida Trabalhador Sancarlense 400, BR-13560-970 Sao Carlos, Brazil.

出版信息

Bioorg Med Chem Lett. 2020 Sep 15;30(18):127420. doi: 10.1016/j.bmcl.2020.127420. Epub 2020 Jul 17.

DOI:10.1016/j.bmcl.2020.127420

PMID:32763808

Abstract

A library of cathepsin S inhibitors of the dipeptide nitrile chemotype, bearing a bioisosteric sulfonamide moiety, was synthesized. Kinetic investigations were performed at four human cysteine proteases, i.e. cathepsins S, B, K and L. Compound 12 with a terminal 3-biphenyl sulfonamide substituent was the most potent (K = 4.02 nM; selectivity ratio cathepsin S/K = 5.8; S/L = 67) and 24 with a 4'-fluoro-4-biphenyl sulfonamide substituent the most selective cathepsin S inhibitor (K = 35.5 nM; selectivity ratio cathepsin S/K = 57; S/L = 31). In silico design and biochemical evaluation emphasized the impact of the sulfonamide linkage on selectivity and a possible switch of P2 and P3 substituents with respect to the occupation of the corresponding binding sites of cathepsin S.

摘要

我们合成了一系列二肽腈类半胱氨酸蛋白酶 S 抑制剂库，这些抑制剂带有生物等排磺酰胺部分。我们在四种人类半胱氨酸蛋白酶（即组织蛋白酶 S、B、K 和 L）上进行了动力学研究。带有末端 3-联苯磺酰胺取代基的化合物 12 是最有效的（K = 4.02 nM；对组织蛋白酶 S/K 的选择性比值为 5.8；S/L 为 67），而带有 4'-氟-4-联苯磺酰胺取代基的化合物 24 是最具选择性的组织蛋白酶 S 抑制剂（K = 35.5 nM；对组织蛋白酶 S/K 的选择性比值为 57；S/L 为 31）。基于计算机的设计和生化评估强调了磺酰胺键对选择性的影响，以及 P2 和 P3 取代基相对于组织蛋白酶 S 相应结合位点占据的可能变化。