Karolina Ersmark

Computational inhibitor design against malaria plasmepsins

Abstract.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.

Microwave-Accelerated Synthesis of Protease Inhibitors

Controlled microwave heating has recently emerged as an enabling and productivity-enhancing tool for the medicinal chemist. With this superheating method, reaction times can often be reduced from days and hours down to minutes, and chemistry previously considered impractical or unattainable can be accessed. In this review, the search for new protease inhibitors using microwave-assisted small-scale organic transformations is presented, with a special focus on the development of inhibitors of the aspartic proteases plasmepsin I, plasmepsin II, and HIV-1 protease. A series of rapid lead-optimizations starting from transition-state mimicking core scaffolds using mainly microwave-accelerated, palladium-catalyzed coupling reactions are presented. Biological background and test results are summarized.