Inhibitors of proteases and amide hydrolases that employ an α-ketoheterocycle as a key enabling functionality

Maryanoff, Bruce E.; Costanzo, Michael J.

doi:10.1016/j.bmc.2007.11.015

Cited by 66 publications

(65 citation statements)

References 151 publications

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“…38 0957-4166/$ -see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2010.02.008 Furthermore, the role of piperazines and diketopiperazines as efficient chiral ligands in enantioselective catalysis has been also examined.…”

Section: Introductionmentioning

confidence: 96%

Mastering chiral substituted 2-oxopiperazines

Risi¹,

Pelà²,

Pollini³

et al. 2010

Tetrahedron: Asymmetry

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Section: Introductionmentioning

confidence: 96%

Mastering chiral substituted 2-oxopiperazines

Risi¹,

Pelà²,

Pollini³

et al. 2010

Tetrahedron: Asymmetry

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“…Thermodynamic stabilization of the corresponding tetrahedral complex (TC) formed between the inhibitor and the attacking nucleophile [11] is exploited for the design of reversible enzyme mechanism based inhibitos. [2,6,[12][13][14][15] Depending on the protease family, the nucleophile could be either an oxygen or a sulfur atom. The sulfhydryl anion of Cys has significantly lower potential to stabilize an anionic TC in comparison with the hydroxide anion because of the larger extent of electron back-donation from the HOMO of the electrophilic CS of the inhibitor to the LUMO of the attacking Cys nucleophile.…”

Section: Introductionmentioning

confidence: 99%

Application of EMBM to Structure‐Based Design of Warheads for Protease Inhibitors

Traube

Shokhen

Albeck

2013

Molecular Informatics

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Most CADD tools handle non-covalent enzyme inhibitors, despite the growing interest of the pharma industry in covalent inhibitors. We have recently introduced an enzyme mechanism-based method, EMBM, as a computational tool for binding trend analysis and prediction of chemical sites (CS) of reversible covalent enzyme inhibitors. In the current study we demonstrate the utility of EMBM to structure-based applications. In this mode, the energy of the enzyme-inhibitor covalent bond is accounted for by the W1 and W2 covalent descriptors we have developed, whereas the non-covalent interactions between the inhibitor CS and the enzyme active site can be estimated directly on the 3D structure of the enzyme-inhibitor complex.

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“…Notably, these inhibitors possess several distinct backbones with moderate to good activity against HCV (Maryanoff and Costanzo, 2008;Ö rtqvist et al, 2010;Lampa et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Novel isomannide-based peptide mimetics containing a tartaric acid backbone as serine protease inhibitors

et al. 2014

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Hepatitis C viral infection is a cause of chronic liver disease, and current therapies are only effective in 50 % of patients. Serine proteases, which are present in both hepatitis C virus (HCV) and the dengue virus, are the most studied class of proteolytic enzymes and are the primary targets for drug development in this field. In this paper, we describe the synthesis of a novel class of isomannide-based peptide mimetic compounds based on a tartaric acid backbone. Our data showed that substitutions at position 168 (D168A) and 170 (V170A) conferred lowlevel resistance against compound 5a3, whereas substitutions at position 155 (R155K) and 156 (A156V) conferred no resistance. These data suggest that even though compound 5a3 is a noncompetitive inhibitor; it is able to interact with important residues located near the catalytic site. In addition, this novel compound class exhibits potent antiviral activity against variants carrying resistance mutations to boceprevir and telaprevir. Our docking studies showed important interactions, including hydrogen bonds and a p-p interaction, between compound 5a3 and residues of the allosteric site of NS3/4A. Biological and theoretical results indicate that 5a3 is a promising lead compound for the development of new drugs targeting HCV infection.

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Inhibitors of proteases and amide hydrolases that employ an α-ketoheterocycle as a key enabling functionality

Cited by 66 publications

References 151 publications

Mastering chiral substituted 2-oxopiperazines

Mastering chiral substituted 2-oxopiperazines

Application of EMBM to Structure‐Based Design of Warheads for Protease Inhibitors

Novel isomannide-based peptide mimetics containing a tartaric acid backbone as serine protease inhibitors

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