Peptidyl epoxides extended in the P′ direction as cysteine protease inhibitors: Effect on affinity and mechanism of inhibition

Perlman, Nurit; Hazan, Maya; Shokhen, Michael; Albeck, Amnon

doi:10.1016/j.bmc.2008.08.031

Cited by 11 publications

(7 citation statements)

References 45 publications

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“…Few methods for preparing the cis -Apa are described and they typically require an amination step from the corresponding diacid, made from sequential oxidations of 1,4-cyclohexadiene . A different synthesis proposes the formation of the diacid in two steps from the hex-3-yne-1,6-diol; the yields for the corresponding hydrogenation and reduction are not reported.…”

Section: Resultsmentioning

confidence: 99%

cis-Apa: A Practical Linker for the Microwave-Assisted Preparation of Cyclic Pseudopeptides via RCM Cyclative Cleavage

et al. 2011

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A new linker cis-5-aminopent-3-enoic acid (cis-Apa) was prepared for the synthesis of cyclic pseudopeptides by cyclization-cleavage by using ring-closing methatesis (RCM). We developed a new synthetic pathway for the preparation of the cis-Apa linker that was tested in the cyclization-cleavage process of different RGD peptide sequences. Different macrocyclic peptidomimetics were prepared by using this integrated microwave-assisted method, showing that the readily available cis-Apa amino acid is well adapted as a linker in the cyclization-cleavage process.

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Section: Resultsmentioning

confidence: 99%

cis-Apa: A Practical Linker for the Microwave-Assisted Preparation of Cyclic Pseudopeptides via RCM Cyclative Cleavage

et al. 2011

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“…Design guided by molecular modeling studies There are numerous precedence indicating that oxiranes are important class of biologically active compounds (33)(34)(35)(36)(37)(38). As PTPs utilize nucleophilic chemistry involving a cysteine residue in turning over their pTyr substrates, they could in principle be covalently inhibited if a suitable pTyr mimic with appropriately positioned electrophilic element is incorporated into the inhibitor design.…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Evaluation of 2‐(arylsulfonyl)oxiranes as Cell‐permeable Covalent Inhibitors of Protein Tyrosine Phosphatases

et al. 2012

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A structure-based design approach has been applied to develop 2-(arylsulfonyl)oxiranes as potential covalent inhibitors of protein tyrosine phosphatases. A detailed kinetic analysis of inactivation by these covalent inhibitors reveals that this class of compounds inhibits a panel of protein tyrosine phosphatases in a time-and dose-dependent manner, consistent with the covalent modification of the enzyme active site. An inactivation experiment in the presence of sodium arsenate, a known competitive inhibitor of protein tyrosine phosphatase, indicated that these inhibitors were active site bound. This finding is consistent with the mass spectrometric analysis of the covalently modified protein tyrosine phosphatase enzyme. Additional experiments indicated that these compounds remained inert toward other classes of arylphosphate-hydrolyzing enzymes, and alkaline and acid phosphatases. Cell-based experiments with human A549 lung cancer cell lines indicated that 2-(phenylsulfonyl)oxirane (1) caused an increase in intracellular pTyr levels in a dose-dependent manner thereby suggesting its cell-permeable nature. Taken together, the newly identified 2-(arylsulfonyl)oxiranyl moiety could serve as a novel chemotype for the development of activity-based probes and therapeutic agents against protein tyrosine phosphatase superfamily of enzymes.

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“…Indeed, many articles report its use in these contexts. 34,[225][226][227][228][229][230][231][232][233][234][235][236][237][238][239][240][241][242][243][244] For example, Aldulaijan and Platts 244 studied the peptide binding to the histocompatibility II receptors. Statistical results indicated a correlation between the half maximal inhibitory concentration (IC 50 ) and RM1-D interaction energy.…”

Section: Biological Chemistrymentioning

confidence: 99%

“…Binding energy estimations of four endo peptidyl epoxide ligands interacting with papain, a cysteine protease enzyme, were carried out in the paper of Perlman et al 226 The authors ran short NPT (constant number of particles, constant-pressure, constant-temperature ensemble) molecular dynamics simulations to produce equilibrated structures for the four papain-inhibitor complexes. Using the time-averaged structures of such complexes, molecular clusters were extracted producing sub-structures of the entire enzyme-inhibitor complexes that contain the inhibitors and the active-site residues of the enzyme.…”

Section: Molecular Dynamicsmentioning

confidence: 99%

RM1 Semiempirical Model: Chemistry, Pharmaceutical Research, Molecular Biology and Materials Science

Lima¹,

Rocha²,

Freire³

et al. 2018

J. Braz. Chem. Soc.

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In this review, we show improvements to the semiempirical quantum chemical method RM1 and present a wide range of its applications as reported by researchers of various areas, such as theoretical, organic, physical, analytical, and inorganic chemistry, as well as their interfaces with medicinal chemistry, biology, and materials science. Success of RM1 is seemingly due to its ability to predict structural, energetic, electronic and wave function dependent properties of the investigated systems, coupled with its low computational demand required to perform calculations when compared to ab initio and density functional methods. Moreover, RM1 is widely available in several computational chemistry softwares, such as MOPAC, GAMESS, Amber, Spartan, HyperChem, and AMPAC. This review describes various case studies that perhaps can be of interest to researchers who might need a more solid basis from which to expand the frontier of applicability of RM1 to even more complex problems on larger systems.

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Peptidyl epoxides extended in the P′ direction as cysteine protease inhibitors: Effect on affinity and mechanism of inhibition

Cited by 11 publications

References 45 publications

cis-Apa: A Practical Linker for the Microwave-Assisted Preparation of Cyclic Pseudopeptides via RCM Cyclative Cleavage

cis-Apa: A Practical Linker for the Microwave-Assisted Preparation of Cyclic Pseudopeptides via RCM Cyclative Cleavage

Design, Synthesis, and Evaluation of 2‐(arylsulfonyl)oxiranes as Cell‐permeable Covalent Inhibitors of Protein Tyrosine Phosphatases

RM1 Semiempirical Model: Chemistry, Pharmaceutical Research, Molecular Biology and Materials Science

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