Crystal Morphology Tools used in the Fight Against Malaria
Researchers at the Weizmann Institute of Science, Israel, and Transform Pharmaceuticals, MA, have used crystal morphology-predicting tools to study quinoline binding sites on malaria pigment crystals, the by-products of hemoglobin digestion by the malaria parasite.
Professor Leiserowitz and team modeled the crystal formation of the malaria pigment and used this information to propose binding sites for quinoline-based anti-malarial drugs.
The work is reported in the journal Crystal Growth & Design , published by the American Chemical Society, 2002, vol. 2, pages 553-562.
Malaria, one of the world's most infectious and deadly diseases, was once thought eradicated. However, with parasitical resistance to common anti-malarial drugs, the disease has re-emerged with a vengeance (300 - 500 million cases with 1-3 million deaths per year). A better understanding of anti-malarial drugs modes of action is thus highly desirable to combat this lethal killer.
Dr R. Buller and Professor L. Leiserowitz at the Weizmann Institute of Science, Israel, and Dr's M. Peterson and O. Almarsson at Transform Pharmaceuticals, MA, have used the crystal morphology-predicting tools, Morphology and HP Morphology, to study quinoline binding sites on malaria pigment crystals, the by-products of hemoglobin digestion by the malaria parasite. 1
Heme is released from the blood of the malaria parasite's host as a by-product of hemoglobin digestion. The parasite then makes this heme less toxic to itself by oxidation. This oxidized heme, known as hematin, then precipitates out as sub-micron to micron-sized crystals, hemozoin, so-called malaria pigment, in a process of biomineralization.
The researchers, using a reported powder-crystal structure determination of a synthetic hemozoin, modeled its crystal growth and compared it to the natural pigment. The morphology studies showed them to be very similar. This information was then used to study binding sites for quinoline-based anti-malarial drugs. The studies revealed that the fastest growing (001) crystal faces form the drug binding sites.
A drug molecule bound to the surface of the malaria pigment crystal will inhibit its formation, which results in less heme being removed from the parasite. An increase in the amount of heme, which is toxic to the malaria parasite, is a good news in the fight against this killer disease.
Professor Leiserowitz (The Weizmann Institute of Science), says "This work is vital in the fight against malaria because malaria parasites are becoming increasingly resistant to the various antimalarial quinoline drugs presently on the market."
Professor Leiserowitz continues "Molecular modeling should enable us to synthesize very effective antimalarial drugs, previously done by trial and error, by using various strategies. For example it should now be possible to design drugs that can not only bind strongly to two neighboring molecular sites on the fast-growing top and bottom faces of the malaria pigment crystal, yet also bind to neighboring sites on the well-developed side faces of the crystal. Molecular modeling should also be able to provide a measure of the inhibiting power of the drug and thus the concentration required to retard crystal growth."
1. R. Buller, M. L. Peterson, O. Almarsson, and L. Leiserowitz, J. Crystal Growth & Design , 2002, vol. 2, pages 553-562, and references cited therein.