Designing Ligands for Leishmania, Plasmodium, and Aspergillus N-Myristoyl Transferase with Specificity and Anti-Target-Safe Virtual Libraries

Curr Comput Aided Drug Des. 2018;14(2):131-141. doi: 10.2174/1573409914666180308163231.


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.

Keywords: Aspergillus; Leishmania; N-myristoyl transferase; Plasmodium; antitarget; drug design; leishmaniasis; safety; selective..

MeSH terms

  • Acyltransferases / antagonists & inhibitors*
  • Acyltransferases / chemistry
  • Acyltransferases / metabolism
  • Antiparasitic Agents / chemistry
  • Antiparasitic Agents / pharmacology*
  • Aspergillosis / drug therapy
  • Aspergillus / drug effects
  • Aspergillus / enzymology*
  • Drug Design*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Leishmania / drug effects
  • Leishmania / enzymology*
  • Leishmaniasis / drug therapy
  • Libraries, Digital
  • Ligands
  • Malaria / drug therapy
  • Molecular Docking Simulation
  • Plasmodium / drug effects
  • Plasmodium / enzymology*


  • Antiparasitic Agents
  • Enzyme Inhibitors
  • Ligands
  • Acyltransferases
  • glycylpeptide N-tetradecanoyltransferase