Title:Designing Ligands for Leishmania, Plasmodium, and Aspergillus N-Myristoyl Transferase with Specificity and Anti-Target-Safe Virtual Libraries
VOLUME: 14 ISSUE: 2
Author(s):Alfonso T. Garcia-Sosa*
Affiliation:Institute of Chemistry, University of Tartu, Ravila 14a, Tartu 50411
Keywords:Leishmania, leishmaniasis, Plasmodium, Aspergillus, N-myristoyl transferase, drug design, safety, selective, antitarget.
Abstract:Background: Leishmaniasis, malaria, and fungal diseases are burdens on individuals and
populations and can present severe complications. Easily accessible chemical treatments for these
diseases are increasingly sought-after. Targeting the parasite N-myristoyl transferase while avoiding
the human enzyme and other anti-targets may allow the prospect of compounds with pan-activity
against these diseases, which would simplify treatments and costs. Developing chemical libraries,
both virtual and physical, that have been filtered and flagged early on in the drug discovery process
(before virtual screening) could reduce attrition rates of compounds being developed and failing late
in development stages due to problems of side-effects or toxicity.
Methods: Chemical libraries have been screened against the anti-targets pregnane-X-receptor, sulfotransferase,
cytochrome P450 2a6, 2c9, and 3a4 with three different docking programs. Statistically
significant differences are observed in their interactions with these enzymes as compared to
small molecule drugs and bioactive non-drug datasets.
Results and Conclusion: A series of compounds are proposed with the best predicted profiles for
inhibition of all parasite targets while sparing the human form and anti-targets. Some of the topranked
compounds have confirmed experimental activity against Leishmania, and highlighted are
those compounds with best properties for further development.
