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Molecular modeling and dynamics studies of purine nucleoside phosphorylase from Bacteroides fragilis
Ivani Pauli Luis Fernando Saraiva Macedo Timmers Rafael Andrade Caceres Luiz Augusto Basso Diógenes Santiago Santos Walter Filgueira de Azevedo Jr. 《Journal of molecular modeling》2009,15(8):913-922
Purine nucleoside phosphorylase (PNP) catalyzes the reversible phosphorolysis of N-ribosidic bonds of purine nucleosides and deoxynucleosides, except adenosine, to generate ribose 1-phosphate and the purine
base. This work describes for the first time a structural model of PNP from Bacteroides fragilis (Bf). We modeled the complexes of BfPNP with six different ligands in order to determine the structural basis for specificity of these ligands against BfPNP. Comparative analysis of the model of BfPNP and the structure of HsPNP allowed identification of structural features responsible for differences in the computationally determined ligand affinities.
The molecular dynamics (MD) simulation was assessed to evaluate the overall stability of the BfPNP model. The superposition of the final onto the initial minimized structure shows that there are no major conformational
changes from the initial model, which is consistent with the relatively low root mean square deviation (RMSD). The results
indicate that the structure of the model was stable during MD, and does not exhibit loosely structured loop regions or domain
terminals. 相似文献
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Guy Barros Barcellos Rafael Andrade Caceres Walter Filgueira de Azevedo Jr. 《Journal of molecular modeling》2009,15(2):147-155
Bacillus anthracis has been employed as an agent of bioterrorism, with high mortality, despite anti-microbial treatment, which strongly indicates
the need of new drugs to treat anthrax. Shikimate pathway is a seven step biosynthetic route which generates chorismic acid
from phosphoenol pyruvate and erythrose-4-phosphate. Chorismic acid is the major branch point in the synthesis of aromatic
amino acids, ubiquinone, and secondary metabolites. The shikimate pathway is essential for many pathological organisms, whereas
it is absent in mammals. Therefore, these enzymes are potential targets for the development of nontoxic antimicrobial agents
and herbicides and have been submitted to intensive structural studies. The forth enzyme of this pathway is responsible for
the conversion of dehydroshikimate to shikimate in the presence of NADP. In order to pave the way for structural and functional
efforts toward development of new antimicrobials we describe the molecular modeling of shikimate dehydrogenase from Bacillus anthracis complexed with the cofactor NADP. This study was able to identify the main residues of the NADP binding site responsible
for ligand affinities. This structural study can be used in the design of more specific drugs against infectious diseases. 相似文献
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Yunpeng Shen Masayo Morishita Doohyun Lee Shinae Kim Taeho Lee Damiaan E.H.F. Mevius Yeonjeong Roh Eric di Luccio 《Biochemical and biophysical research communications》2019,508(1):102-108
The NSD family (NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1) are histone lysine methyltransferases (HMTases) essential for chromatin regulation. The NSDs are oncoproteins, drivers of a number of tumors and are considered important drug-targets but the lack of potent and selective inhibitors hampers further therapeutic development and limits exploration of their biology. In particular, MMSET/NSD2 selective inhibition is being pursued for therapeutic interventions against multiple myeloma (MM) cases, especially in multiple myeloma t(4;14)(p16.3;q32) translocation that is associated with a significantly worse prognosis than other MM subgroups. Multiple myeloma is the second most common hematological malignancy, after non-Hodgkin lymphoma and remains an incurable malignancy.Here we report the discovery of LEM-14, an NSD2 specific inhibitor with an in vitro IC50 of 132?μM and that is inactive against the closely related NSD1 and NSD3. LEM-14-1189, a LEM-14 derivative, differentially inhibits the NSDs with in vitro IC50 of 418?μM (NSD1), IC50 of 111?μM (NSD2) and IC50 of 60?μM (NSD3). We propose LEM-14 and derivative LEM-14-1189 as tools for studying the biology of the NSDs and constitute meaningful steps toward potent NSDs therapeutic inhibitors. 相似文献
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