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

Bioorganic and Medicinal Chemistry

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

  Jones, Matthew A ^a   Morton, James D ^b   Coxon, James M ^a   McNabb, Stephen B ^a   Lee, Hannah Y Y ^b   Aitken, Steven G ^a   Mehrtens, Janna M ^a   Robertson, Lucinda J G ^b   Neffe, Axel T ^a   Miyamoto, Shigeru ^a   Bickerstaffe, Roy ^b   Gately, Karl ^b   Wood, Jacqueline M ^b   Abell, Andrew D ^a  

^a UNIVERSITY OF CANTERBURY   (New Zealand)

^b LINCOLN UNIVERSITY   (New Zealand)

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;

AMINO ACID SEQUENCE; ARTICLE; CRYSTAL STRUCTURE; DRUG ACTIVITY; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; IN VITRO STUDY; MOLECULAR MODEL; NONHUMAN; NUCLEAR MAGNETIC RESONANCE; NUCLEOTIDE SEQUENCE; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

ALDEHYDES; ANIMALS; BINDING SITES; DIPEPTIDES; GLYCOPROTEINS; HUMANS; MODELS, MOLECULAR; SHEEP; STRUCTURE-ACTIVITY RELATIONSHIP;

OVIS;

EID: 47349126656     PISSN: 09680896     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmc.2008.05.048     Document Type: Article

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35. 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. 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. 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. 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. 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.
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41. Glide Einternal score is the internal strain energy of the ligand.
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