Computational inhibitor design against malaria plasmepsins
2007 (English)In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 64, no 17, 2285-2305 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2007. Vol. 64, no 17, 2285-2305 p.
Malaria, plasmepsin, inhibitor design, reaction mechanism, molecular dynamics, linear interaction energy method
IdentifiersURN: urn:nbn:se:uu:diva-96524DOI: 10.1007/s00018-007-7102-2ISI: 000249204800011OAI: oai:DiVA.org:uu-96524DiVA: diva2:171126