Identification of Dipeptidyl Nitriles as Potent and Selective Inhibitors of Cathepsin B through Structure-Based Drug Design

Abstract

Cathepsin B is a member of the papain superfamily of cysteine proteases and has been implicated in the pathology of numerous diseases, including arthritis and cancer. As part of an effort to identify potent, reversible inhibitors of this protease, we examined a series of dipeptidyl nitriles, starting with the previously reported Cbz-Phe-NH-CH(2)CN (19, IC(50) = 62 microM). High-resolution X-ray crystallographic data and molecular modeling were used to optimize the P(1), P(2), and P(3) substituents of this template. Cathepsin B is unique in its class in that it contains a carboxylate recognition site in the S(2)' pocket of the active site. Inhibitor potency and selectivity were enhanced by tethering a carboxylate functionality from the carbon alpha to the nitrile to interact with this region of the enzyme. This resulted in the identification of compound 10, a 7 nM inhibitor of cathepsin B, with excellent selectivity over other cysteine cathepsins.

Design, Synthesis and In-Silico Studies of Novel Chalcones as Anti-Prostate Cancer and Cathepsin B Inhibitors

“…In this work, the synthesis of a small library of chalcones and a study of their role as inhibitors of cathepsin B was carried out. First, the protocol of the docking was validated by reproducing the binding structure of the DPN ligand to active site of cathepsin B protein in the crystal complex (PDB code: 1GMY) (Greenspan et al, 2001), fig. 5.…”

“…High mortality rate in patients could be mainly attributed to the invasiveness and metastasis in the prostate cancer progression. Generally, malignant cells show an increased rate of proteolytic activity, thus resulting in enhanced invasion and metastasis (Heidenreich et al, 2008;Fidler 1990). Many proteolytic enzymes are involved in the degradation of the extracellular matrices.…”

Inhibitors of Proteinases as Potential Anti-Cancer Agents

“…A wide variety of these inhibitors were obtained using computer-aided design. For example, high-resolution X-ray crystallographic data and molecular modeling studies were used to find out one of the most potent inhibitors of cathepsin B (K i =7nM) -dipeptide nitrile shown in Figure 8 (Greenspan et al, 2001). In the Figure www.intechopen.com…”

Crystallographic, DFT and docking (cathepsin B) studies on an organotellurium(IV) compound

“…The lysosomal cysteine protease, Cathepsin B, hereafter Cat B, is responsible for the degradation and processing of proteins in living organisms [1,2]. The structure is characterised by a thiol in the cysteine residue, Cys29, and a histidine, His199, in the catalytic site [3,4], and therefore, in the context of metal-based drugs, offers the opportunity for coordination to metal centres.…”