Zhang Yue Zhou

University of Helsinki
Supervisor: Henri Xhaard
Funding: other
Date: 2010-01-01

Computational approaches to develop anti-Leishmanial compounds

The leishmaniases are diseases caused by protozoan parasites that affect millions of people in more than 88 countries world-wide. The parasite causes three main forms of clinical disease: i) visceral leishmaniasis, the most severe form is usually fatal if not treated and affects internal organs such as the liver, spleen and bone marrow; ii) mucocutaneous leishmaniasis, a chronic form of that causes extensive destruction and disfiguring of the nasopharynx region; and iii) cutaneous leishmaniasis the mildest form, usually self-cures within a few months to years causing scarring at the site of the lesion(s).

As to date, there is an urgent need for the development and testing of new compounds for the treatment of all clinical forms of leishmaniasis. The current drugs, pentamidine or amphotericin B are administrated by injection and require clinical supervision or hospitalization due the possibility of severe side effects. Parasite resistance to pentavalent antimony drugs has moreover resulted in discontinued use of these compounds in some endemic regions for visceral leishmaniasis. Liposomal amphotericin B shows reduced toxicity but is prohibitively expensive for use in less-developed countries. Recently, miltefosine, an alkylphospholipid derivative and the first orally administered drug has entered phase IV clinical studies and been registered for use in India. However, the teratogenic effects of this drug prevent its use in pregnant women.

Recently, the medicinal chemistry group of the Faculty of Pharmacy in the University of Helsinki has synthesized a library of >300 compounds and some compound classes have shown potent antileishmanial activity in axenic amastigotes of Leishmania donovani. These compounds are synthetic nitrogen-containing heterocycles (triazolidines), synthetic derivatives of natural products, such as abundant, naturally occurring terpenes, betulin (from Betula sp.) (1,2,3)and abietanes (from Pinus sp. and Picea sp.).

Using a set of SAR series of 300 compounds, as well as other known molecules, I will use ligand-based computational methods to define the relative importance of functional chemical groups towards antileishmanial activity. I will elaborate pharmacophoric representations of these molecules that will be useful for screening. I will be involved in building and analyzing of our databases of compounds. A more difficult aim will be, when I has acquired sufficient knowledge in chemoinformatics, to be involved in suggesting molecular targets potentially involved in interactions with our anti-Leishmania compounds.