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Theoretical study of peptide deformylase inhibitors

Author: WangHuanJie
Tutor: FengDaCheng
School: Shandong University
Course: Physical and chemical
Keywords: PDF ( peptide deformylase enzyme) Molecular Docking Molecular dynamics simulation Density functional theory
CLC: TQ460.1
Type: Master's thesis
Year: 2007
Downloads: 61
Quote: 0
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Abstract


Peptide the demethyl-acylase (PDF) is a bacterial necessary metalloenzymes play take off from the methionine residue at N terminal formyl role in protein synthesis. PDF bacterial growth and protein synthesis necessary for an enzyme protein synthesis in eukaryotic cells, but it is not necessary, so PDF potential target for new antibiotics has become by far the most promising antibiotic agents. a. As a metal enzyme the PDF inhibitor design methodology has become better mechanism-based rational drug design. People use enzyme structure and mechanism of information, coupled with high-throughput screening method to determine the types of valid PDF inhibitors. Most PDF inhibitors have the general structural characteristics of a 'ion binding domain peptide analogues'. However, there is still an urgent need for the development of new and different structure of the non-peptide PDF inhibitor. Therefore, we designed a series of PDF inhibitors and molecular modeling and quantum mechanics to study its mode of action and PDF. The main contents are as follows: First with VectorNT software to existing PDF enzyme sequence classification using the the SPDV software skeleton superimposed, select 1BSK as a receptor for molecular docking, ligand design according to the literature The skeleton of the benzene ring and the furan ring compounds, SYBYL7.0 using FlexX method Run multiple ligand module docking docking score and the analysis of the mode of action has been way better compounds with the PDF enzyme 1BSK combination. Secondly, the preferred way of selective binding compounds as well as activity data PDF inhibitors molecular dynamics simulation software Tinker program package, and the compound was divided into three fragments (ion-binding region, the skeleton The area and the modified zone) is calculated separately for each fragment with the amino acids around the role and activity data were compared and examined in detail the mode of action of each fragment. Finally, DFT B3LYP study the different ionic PDF simplified model of the enzyme active site, as well as a simplified model of the hydrolysis of the PDF catalytic polypeptide results show that on the Zn 2 , the Fe 2 and Ni 2 three PDF, the Zn 2 -PDF is the most unstable, formamide and N-hydroxy H 2 O and PDF binding complex stability, N-hydroxy carboxamide can be used as the PDF inhibitors substituted PDF, H 2 O on the location combined with the PDF, thereby inhibiting the hydrolysis of PDF polypeptide. Formamide hydrolysis of model compounds via two paths: collaborative mechanism and step-by-step reaction mechanism, both the activation energy of the reaction mechanism is little difference of 39.58 kcal / mol and 39.56 kcal / mol. In order to consider the impact of the PDF hydrolysis of formamide, we also used a semi-empirical method PM3 PDF catalytic formamide de-formyl model were studied. The peptide deformylase process in living systems is very complex, in order to further understand the reaction mechanism of the process, follow-up work needs to carry out to meet the development of new and different structure of the PDF inhibitors urgent need to.

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