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Volumn 16, Issue 14, 2008, Pages 6911-6923

Synthesis, biological evaluation and molecular modelling of N-heterocyclic dipeptide aldehydes as selective calpain inhibitors

Author keywords

Calpain; CAT0059; In silico calpain homology model; Isoform selectivity; Ovine calpain 1 and 2; Substituted heterocyclic dipeptides

Indexed keywords

1H PYRROLE 2 CARBOXYLIC ACID [(1 FORMYL 3 METHYL BUTYLCARBAMOYL) 2 METHYL PROPYL] AMIDE; 4 FORMYL 1H PYRROLE 2 CARBOXYLIC ACID [(1 FORMYL 3 METHYL BUTYLCARBAMOYL) 2 METHYL PROPYL] AMIDE; 5 [(1 FORMYL 3 METHYL BUTYLCARBAMOYL) 2 METHYL PROPYLCARBAMOYL] 1H PYRROLE 2 CARBOXLIC ACID METHYL ESTER; 5 FORMYL 1 METHYL 1H PYRROLE 2 CARBOXYLIC ACID [(1 FORMYL 3 METHYL BUTYLCARBAMOYL) 2 METHYL PROPYL] AMIDE; 5 FORMYL FURAN 2 CARBOXYLIC ACID [(1 FORMYL 3 METHYL BUTYLCARBAMOYL) 2 METHYL PROPYL] AMIDE; 5 FORMYL PYRROLE; 5 FORMYL PYRROLE 2 CARBOXYLIC ACID [(1 FORMYL 3 METHYL BUTYLCARBAMOYL) 2 METHYL PROPYL] AMIDE; 5 FORMYL THIOPHENE 2 CARBOXYLIC ACID [(1 FORMYL 3 METHYL BUTYLCARBAMOYL) 2 METHYL PROPYL] AMIDE; 5 METHYL 1H PYRROLE 2 CARBOXYLIC ACID [(1 FORMYL 3 METHYL BUTYLCARBAMOYL) 2 METHYL PROPYL] AMIDE; ALDEHYDE DERIVATIVE; CALPAIN 1; CALPAIN 2; CALPASTATIN; CAT 0059; FURAN 2 CARBOXYLIC ACID [(1 FORMYL 3 METHYL BUTYLCARBAMOYL) 2 METHYL PROPYL] AMIDE; THIOPHENE 2 CARBOXYLIC ACID [(1 FORMYL 3 METHYL BUTYLCARBAMOYL) 2 METHYL PROPYL] AMIDE; UNCLASSIFIED DRUG;

EID: 47349126656     PISSN: 09680896     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmc.2008.05.048     Document Type: Article
Times cited : (22)

References (42)
  • 17
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    • note
    • Optimal yield of the desired dipeptide alcohols 16-20 was obtained using 1.2 equiv of 15.
  • 30
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    • note
    • PBD file numbers: 1MDW, 1TL9, 1TLO, 1KXR, 2G8J, 2G8E, 2NQG, 2NQI, 2ARY, 1ZCM.
  • 33
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    • MacroModel, version 9.1, Schrödinger, LLC, New York, NY, 2005.
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    • note
    • 271. Recent X-ray crystal structures, for example, SNJ1715 co-crystallised with r-CAPN1 construct (PDB code 2G8E), confirm the importance of these hydrogen bonds. These hydrogen bonds equate to the hydrogen bonds labelled A, B and C as reported in Table 2.
  • 36
    • 47349129543 scopus 로고    scopus 로고
    • note
    • The Leu amide in all of the docked compounds 4-13 is trans in all poses. We did not limit the programme to collecting only poses where the amide(s) is trans and for some poses the Val amine is in a cis configuration.
  • 37
    • 47349118130 scopus 로고    scopus 로고
    • note
    • Of the 84 poses generated for inhibitor 8 docked in the o-CAPN1 and o-CAPN2 models, 72 gave the carbonyl carbon of the aldehyde in proximity to the active site cysteine (<4.5 Å). Of these 72 poses 42 exhibited a β-strand arrangement of the inhibitor and 20 of these had the Val amide in a trans configuration.
  • 38
    • 47349118418 scopus 로고    scopus 로고
    • note
    • Of the 32 poses generated for inhibitor 9 docked in o-CAPN2 model only six gave the carbonyl carbon of the aldehyde in proximity to the active site cysteine (<4.5 Å). Of these six poses five including the lowest energy poses were in the shunted arrangement with only a single pose with the inhibitor in a more common binding mode as defined by hydrogen bonds A, B and C.
  • 39
    • 47349126247 scopus 로고    scopus 로고
    • note
    • The 5-formyl-pyrrole 9 possesses two aldehyde groups. Only two of the 72 poses collected in the docking studies with o-CANP1 and o-CANP2 show the pyrrole aldehyde in proximity to the active site cysteine sulfur (<4.5 Å). Thirty-three poses have the Leu aldehyde in proximity to the active site cysteine sulfur. Furthermore, the Leu aldehyde is the more reactive to nucleophilic attack since the nitrogen of the pyrrole aldehyde reduces the electrophilic character of the carbonyl. The dialdehyde 9 reacts with hydroxylamine only at the Leu aldehyde. This supports the Leu aldehyde as being responsible for the potency of 9.
  • 40
    • 47349089510 scopus 로고    scopus 로고
    • note
    • Glide Emodel combines the energy grid score, the binding affinity predicted by the GlideScore and the internal strain energy of the ligand for the model potential used to direct the conformational-search algorithm.
  • 41
    • 47349110743 scopus 로고    scopus 로고
    • note
    • Glide Einternal score is the internal strain energy of the ligand.
  • 42
    • 47349124951 scopus 로고    scopus 로고
    • Abell, A. D.; Coxon, J. M.; Miyamoto, S.; Jones, M. A.; Neffe, A. T.; Aitken, S. G.; Stuart, B. G.; Nikkel, J. M.; Morton, J. D.; Bickerstaffe, R.; Robertson, L. J.; Lee, H. Y.; Muir. M. S. N.Z. Patent. 2007, 547303; U.S. Patent Appl., 2007, 20070293560.
    • Abell, A. D.; Coxon, J. M.; Miyamoto, S.; Jones, M. A.; Neffe, A. T.; Aitken, S. G.; Stuart, B. G.; Nikkel, J. M.; Morton, J. D.; Bickerstaffe, R.; Robertson, L. J.; Lee, H. Y.; Muir. M. S. N.Z. Patent. 2007, 547303; U.S. Patent Appl., 2007, 20070293560.


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.