abstract
There is a high demand for new drugs against malaria, which takes millions of lives annually. The abuse of classical antimalarials from the late 1940's to the early 1980's has bred resistant parasites, which led to the use of more potent drugs that ended up by refueling the resistance cycle. An example is chloroquine, once highly effective but now virtually useless against malaria. Structure-based rational drug design relies on high-resolution target structures to allow for screening of selective ligands/inhibitors. For the past two decades, and especially after the unveiling of the Plasmodium falciparum genome in 2002, enzymes of this lethal malaria parasite species have been increasingly attracting the attention of Medicinal Chemists worldwide as promising drug targets. There is particular emphasis on proteases having key roles on the degradation of host's hemoglobin within the food vacuole of blood-stage parasites, as these depend on such process for their survival. Among such enzymes, Plasmepsins (aspartic proteases) and, especially, Falcipains (cysteine proteases) are highly promising antimalarial drug targets. The present review will focus on the computational approaches made so far towards the unraveling of the structure, function and inhibition of Falcipains that, by virtue of their quite specific features, are excellent targets for highly selective inhibitors.
keywords
POTENTIAL ANTIMALARIAL AGENTS; ARTEMISININ-RESISTANT MALARIA; HEMOGLOBIN DEGRADATION; GENETIC ALGORITHM; RECOMBINANT FALCIPAIN-2; PROTEINASE-INHIBITORS; MOLECULAR RECOGNITION; TOXOPLASMA-GONDII; ASPARTIC PROTEASE; ACCURATE DOCKING
subject category
Biochemistry & Molecular Biology; Pharmacology & Pharmacy
authors
Teixeira, C; Gomes, JRB; Gomes, P
our authors
Cátia Teixeira
Post-doc Fellowship
José R. B. Gomes
Principal Researcheracknowledgements
We are grateful for the financial support from Fundacao para a Ciencia e a Tecnologia (FCT, Portugal) to CIQ-UP and CICECO, for the Programme Ciencia 2007 and for the Post-doctoral fellowship SFRH/BPD/62967/2009 to Catia Teixeira. We also thank FCT and the European Union (FEDER) for co-funding this Project (refs. PTDC/QUI/65142/2006 and FCOMP-01-0124-FEDER-007418).