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

Carina Lemke; Lorenzo Cianni; Christian Feldmann; Erik Gilberg; Jiafei Yin; Fernanda Dos Reis Rocho; Daniela de Vita; Ulrike Bartz; Jürgen Bajorath; Carlos A Montanari; Michael Gütschow

doi:10.1016/j.bmcl.2020.127420

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

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

Authors

Affiliations

¹ Pharmaceutical Institute, Pharmaceutical and Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
² 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.
³ Bonn Aachen International Center for Information Technology BIT, Life Science Informatics, University of Bonn, Endenicher Allee 19c, D-53115 Bonn, Germany.
⁴ Instituto de Química de Sao Carlos, University of Sao Paulo, Avenida Trabalhador Sancarlense 400, BR-13560-970 Sao Carlos, Brazil.
⁵ Department of Natural Sciences, University of Applied Sciences Bonn-Rhein-Sieg, von-Liebig-Str. 20, D-53359 Rheinbach, Germany.
⁶ Bonn Aachen International Center for Information Technology BIT, Life Science Informatics, University of Bonn, Endenicher Allee 19c, D-53115 Bonn, Germany. Electronic address: bajorath@bit.uni-bonn.de.
⁷ Instituto de Química de Sao Carlos, University of Sao Paulo, Avenida Trabalhador Sancarlense 400, BR-13560-970 Sao Carlos, Brazil. Electronic address: carlos.montanari@usp.br.
⁸ Pharmaceutical Institute, Pharmaceutical and Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany. Electronic address: guetschow@uni-bonn.de.

PMID: 32763808
DOI: 10.1016/j.bmcl.2020.127420

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_i = 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_i = 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.

Keywords: Cathepsin S; Nitriles; Reversible inhibition; Sulfonamides.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Binding Sites
Cathepsin K / metabolism
Cathepsin L / metabolism
Cathepsins / antagonists & inhibitors*
Computer Simulation
Cysteine Proteases / metabolism
Dipeptides / chemical synthesis*
Enzyme Inhibitors / chemical synthesis*
Humans
Kinetics
Nitriles / chemical synthesis*
Protein Binding
Structure-Activity Relationship
Sulfonamides / chemistry*

Substances

Dipeptides
Enzyme Inhibitors
Nitriles
Sulfonamides
Cathepsins
Cysteine Proteases
Cathepsin L
cathepsin S
Cathepsin K