Computational inhibitor design against malaria plasmepsins

Plasmepsins are aspartic proteases involved in the degradation of the host cell hemoglobin that is used as a food source by the malaria parasite. Plasmepsins are highly promising as drug targets, especially when combined with the inhibition of falcipains that are also involved in hemoglobin cataboli...

Full description

Saved in:
Bibliographic Details
Published in:Cellular and molecular life sciences : CMLS 2007-09, Vol.64 (17), p.2285-2305
Main Authors: Bjelic, S, Nervall, M, Gutiérrez-de-Terán, H, Ersmark, K, Hallberg, A, Åqvist, J
Format: Article
Language:English
Subjects:
Animals
Antimalarials - chemistry
Antimalarials - pharmacology
Aspartic Acid Endopeptidases - antagonists & inhibitors
Aspartic Acid Endopeptidases - chemistry
Aspartic Acid Endopeptidases - metabolism
Binding Sites
Biochemistry
Biokemi
Biologi
Biology
Computational Biology - methods
Crystal structure
Crystallography, X-Ray
Drug Design
Humans
inhibitor design
linear interaction energy method
Malaria
Models, Molecular
Molecular biology
molecular dynamics
NATURAL SCIENCES
NATURVETENSKAP
Parasites
plasmepsin
Plasmodium - drug effects
Plasmodium - enzymology
Protease Inhibitors - chemistry
Protease Inhibitors - pharmacology
Proteases
Protein Structure, Tertiary
reaction mechanism
Review
Vector-borne diseases
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Plasmepsins are aspartic proteases involved in the degradation of the host cell hemoglobin that is used as a food source by the malaria parasite. Plasmepsins are highly promising as drug targets, especially when combined with the inhibition of falcipains that are also involved in hemoglobin catabolism. In this review, we discuss the mechanism of plasmepsins I-IV in view of the interest in transition state mimetics as potential compounds for lead development. Inhibitor development against plasmepsin II as well as relevant crystal structures are summarized in order to give an overview of the field. Application of computational techniques, especially binding affinity prediction by the linear interaction energy method, in the development of malarial plasmepsin inhibitors has been highly successful and is discussed in detail. Homology modeling and molecular docking have been useful in the current inhibitor design project, and the combination of such methods with binding free energy calculations is analyzed.
ISSN:1420-682X
1420-9071
1420-9071
DOI:10.1007/s00018-007-7102-2