Synthesis, bioactivity, theoretical and molecular docking study of 1-cyano-N-substituted-cyclopropanecarboxamide as ketol-acid reductoisomerase inhibitor

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 13, 2007, Pages 3784-3788

  Liu, Xing Hai ^a   Chen, Pei Quan ^a   Wang, Bao Lei ^a   Li, Yong Hong ^a   Wang, Su Hua ^a   Li, Zheng Ming ^a  

^a NANKAI UNIVERSITY   (China)

Author keywords

Cyclopropanecarboxamide; KARI; Molecular docking; Structure; Synthesis; Theoretical study

Indexed keywords

CYCLOPROPANE DERIVATIVE; KETOL ACID REDUCTOISOMERASE; OXIDOREDUCTASE INHIBITOR;

AMINO ACID SYNTHESIS; ARTICLE; BINDING AFFINITY; BIOSYNTHESIS; CRYSTAL STRUCTURE; DRUG BINDING; DRUG STRUCTURE; INFRARED SPECTROSCOPY; MASS SPECTROMETRY; PROTON NUCLEAR MAGNETIC RESONANCE; RICE; SPINACH; STRUCTURE ANALYSIS; X RAY CRYSTALLOGRAPHY;

BINDING SITES; CHEMISTRY, PHARMACEUTICAL; CRYSTALLOGRAPHY, X-RAY; CYCLOPROPANES; DRUG DESIGN; ENZYME INHIBITORS; ESCHERICHIA COLI; KETOL-ACID REDUCTOISOMERASE; KINETICS; LIGANDS; MODELS, CHEMICAL; MODELS, MOLECULAR; MOLECULAR CONFORMATION; ORYZA SATIVA; SPECTROSCOPY, FOURIER TRANSFORM INFRARED;

RUMEX; SPINACIA OLERACEA;

EID: 34250219961     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.04.003     Document Type: Article

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25. All docking procedures were done in NanKai Stars supercomputer at Nankai University. The automated molecular docking calculations were carried out using AutoDock 3.05. The AUTOTORS module of AutoDock defined the active torsions for each docked compound. The active sites of the protein were defined using AutoGrid centred on the IpOHA in the crystal structure. The grid map with 60 × 60 × 60 points centred at the center of mass of the KARI and a grid spacing of 0.375 Å was calculated using the AutoGrid program to evaluate the binding energies between the inhibitors and the protein. The Lamarckian genetic algorithm (LGA) was used as a searching method. Each LGA job consisted of 50 runs, and the number of generation in each run was 27000 with an initial population of 100 individuals. The step size was set to 0.2 Å for translation and 5° for orientation and torsion. The maximum number of energy evaluations was set to 15,00,000. Operator weights for cross-over, mutation and elitism were 0.80, 0.02 and 1, respectively. The docked complexes of the inhibitor-enzyme were selected according to the criterion of interaction energy combined with geometrical and electronic matching quality.
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