Linked Life Data

11765133

Source:http://linkedlifedata.com/resource/pubmed/id/11765133

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2001-12-17
pubmed:abstractText
Plasmodium falciparum is a major causative agent of malaria, a disease of worldwide importance. Inhibition of a hemoglobin degrading P. falciparum aspartic protease Plasmepsin II (Plm II) provides a viable strategy for antimalarial therapy. Linear peptidic inhibitors based on the 4(S)-amino-3(S)-hydroxy-5-phenylpentanoic acid at the P1-P1' positions are known which inhibit Plm II with improved selectivity over cathepsin D. A series of computations were performed in order to gain insight into the interactions of these inhibitors with Plm II. The docking and molecular dynamics simulations were performed on a model ligand/enzyme complex to optimize the variables involved in the generation of ligand/enzyme models. This protocol of docking and molecular dynamics (MD) simulation was then used to derive the ligand-enzyme complexes of the molecules used in the present study. Different modes of binding of pepstatin and the three linear inhibitors were studied. Molecular dynamics simulation was performed at 300K for 100ps with a time step of Ifs. The structural effects of ligand binding were analyzed on the basis of hydrogen bond interactions, interaction energies, hydrophobic contacts and RMS deviations in the resulting energy-minimized structures of the receptor-ligand complexes. The results indicate that hydrophobic and hydrogen bonding interactions are responsible for selective inhibition of Plm II and improved selectivity over cathepsin D. Hydrogen bonding interaction plays an important role for amino acid residues such as Asp-34, Asp-214, Thr-217, Ser-218, Val-78, Ser-79, Tyr-192 and Gly-216. The binding of the inhibitors to the enzyme, while producing no large distortions in the enzyme active site cleft, results in significant RMS deviations of the inhibitor, which represent the distortion of the inhibitor, effected by the proteinase. Thus, the information generated from this analysis should be useful for further work in the area of antimalarial research.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
1055-9612
pubmed:author
pubmed:issnType
Print
pubmed:volume
17
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
293-313
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed:year
2001
pubmed:articleTitle
Molecular dynamics simulations of the three dimensional model of plasmepsin II-peptidic inhibitor complexes.
pubmed:affiliation
Pharmaceutical Division, Department of Chemical Technology, University of Mumbai, India.
pubmed:publicationType
Journal Article