Abstract
Marine trypanocidal natural products are, most often, reported with trypanocidal activity and selectivity against human cell lines. The triaging of hits requires a consideration of chemical tractability for drug development. We utilized a combined Lipinski’s rule-of-five, chemical clustering and ChemGPS-NP principle analysis to analyze a set of 40 antitrypanosomal natural products for their drug like properties and chemical space. The analyses identified 16 chemical clusters with 11 well positioned within drug-like chemical space. This study demonstrated that our combined analysis can be used as an important strategy for prioritization of active marine natural products for further investigation.
Highlights
Human African Trypanosomiasis (HAT), known as African Sleeping Sickness, is a fatal disease transmitted by two species of a protozoan parasite, T. brucei rhodesiense and T. brucei gambiense
The objective was to front-load both crude extracts and subsequent fractions with desirable physicochemical properties, rapidly isolate natural products that are principally located within biologically relevant chemical space, and prioritize isolated compounds for further chemical and biological investigation
Lipinski’s rule-of-five in terms of molecular weight (MW) < 500 Da (92%), log P < 5 (87.5%), hydrogen bond acceptors (HBA) < 10 (97.5%) and hydrogen bond donors (HBD) < 5 (97.5%), we have previously reported that log D5.5 is a more useful parameter to classify the lipophilicity of ionisable natural products [14]
Summary
Human African Trypanosomiasis (HAT), known as African Sleeping Sickness, is a fatal disease transmitted by two species of a protozoan parasite, T. brucei rhodesiense and T. brucei gambiense. The second stage effective drug melarsoprol has associated toxicity which has been reported as lethal in up to 12% of cases [2]. There is an urgent need for the development of new, safer and more effective drugs to fight African Sleeping Sickness. Sanofi-Aventis and Drugs for Neglected Diseases initiative (DNDi) have announced an agreement for the development, manufacturing and distribution of fexinidazole, a promising new drug for the treatment of African Sleeping Sickness [5]. Though natural product research has not played a central role in the search for antitrypanosomal therapeutics, there are emerging numbers of compounds from plants and marine organisms with promising activity against trypanosomiasis [6,7,8]. Natural products research stops when new structures and their associated biological activities are published. We will discuss the chemoinformatic methods we used to conduct the analysis, including Lipinski’s rule-of-five, chemical clustering and ChemGPS-NP principle component analysis, as well as the results of these analyses
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