- Article -
| In Silico Biology 6, 0043 (2006); ©2006, Bioinformation Systems e.V. |
Theoretical study of Escherichia coli peptide deformylase inhibition by several drugs
Abdelouahab Chikhi1,2*, Abderrahmane Bensegueni1, Abderrahmane Boulahrouf2 and Mustapha Bencharif1
1 Laboratory of Materials Chemistry, Department of Chemistry
2 Laboratory of Microbiological Engineering and Applications, Department of Biology
Faculty of Sciences, Mentouri University, Constantine, Algeria
* Corresponding author
Email: abchikhi@yahoo.fr
Edited by E. Wingender; received May 03, 2006; revised August 07, 2006; accepted August 12, 2006; published August 15, 2006
Abstract
Because peptide deformylase (PDF) is essential for the initiation of translation in eubacteria but not in eukaryotes, it is a potentially interesting target for antibiotics. Computer simulation using docking software can be used to model protein-ligand interactions, and in this brief report we describe its use in optimizing the design in PDF-directed inhibitors.
PDF was used as target for a set of five inhibitors with substantial structural differences. Docking results show that the compound 1BB2 (actinonin) binds with high affinity to the enzyme and produces the most stable complex, forming nine hydrogen bonds with the enzyme active site. Its binding energy is ΔG = -31.880 kJ/mol. The modeling study shows that when the methyl group of 1BB2 is replaced with an amine group, the binding energy is increased to -35.316 kJ/mole. This enhancement is more marked (ΔG = -41.141 kJ/mol) when the propyl group and the five-membered ring of 1BB2 are replaced by an amide group and a phenyl ring, respectively.
We describe an attempt to design better antibiotics on the basis of a computer-aided simulation of the interaction between a drug and its target molecule.
Keywords: antibiotic resistance, target, peptide deformylase, antibacterial agents, deformylation, protein maturation, theoretical method, docking software, interactions, cobalt metalloenzyme, FlexX program, binding energy, enzyme-inhibitor complex, hydrogen bonds, modeling, substitution, affinity