CoMFA and HQSAR of acylhydrazide cruzain inhibitors.
An approach combining CoMFA and HQSAR methods was used to describe QSAR models for a series of cruzain inhibitors having the acylhydrazide framework. A CoMFA study using two alignment orientations (I and II), three different probe atoms and changes of the lattice spacing (1 and 2 A) was performed. Alignment II and an sp3 probe carbon atom yielded good cross-validation (q2=0.688) employing lattice spacing of 1 A. The best HQSAR model was generated using atoms, bond, and connectivity as fragment distinction and fragment size default (4-5) showing similar cross-validated value of CoMFA (q2=0.689). Based upon the information derived from CoMFA and HQSAR, we have identified some key features that may be used to design new acylhydrazide derivatives that may be more potent cruzain inhibitors.
Rodrigues
Carlos R
CR
LASSBio, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, 21944-970, Brazil. rangel@pharma.ufrj.br
Flaherty
Terrence M
TM
Springer
Clayton
C
McKerrow
James H
JH
Cohen
Fred E
FE
D000818:Animals; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006834:Hydrazines / Q000737:chemistry* / Q000494:pharmacology*; D021621:Imaging, Three-Dimensional / Q000295:instrumentation / Q000379:methods; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000201:enzymology
D015853:Cysteine Proteinase Inhibitors; D006834:Hydrazines; D008024:Ligands; D015800:Protozoan Proteins; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi