2. Academic Validation
  3. Exploring Subsite Selectivity within Plasmodium vivax N-Myristoyltransferase Using Pyrazole-Derived Inhibitors

Exploring Subsite Selectivity within Plasmodium vivax N-Myristoyltransferase Using Pyrazole-Derived Inhibitors

  • J Med Chem. 2024 May 9;67(9):7312-7329. doi: 10.1021/acs.jmedchem.4c00168.
Diego Rodríguez-Hernández 1 2,  Michael K Fenwick 3 4,  Rachael Zigweid 3 4,  Banumathi Sankaran 5,  Peter J Myler 3 4 6,  Per Sunnerhagen 1,  Alexis Kaushansky 4 6,  Bart L Staker 3 4,  Morten Grøtli 1
Affiliations

Affiliations

  • 1 Department of Chemistry and Molecular Biology, University of Gothenburg, S-405 30 Gothenburg, Sweden.
  • 2 Department of Structural and Functional Biology, Synthetic Biology Laboratory, Institute of Biology, University of Campinas, Campinas, SP 13083-862, Brazil.
  • 3 Seattle Structural Genomics Center for Infectious Disease, Seattle, Washington 98109, United States.
  • 4 Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington 98109, United States.
  • 5 Molecular Biophysics and Integrated Bioimaging, Berkeley Center for Structural Biology, Advanced Light Source, Berkeley National Laboratory, Berkeley, California 94720, United States.
  • 6 Department of Pediatrics, University of Washington, Seattle, Washington 98195, United States.
PMID: 38680035 DOI: 10.1021/acs.jmedchem.4c00168
Abstract

N-myristoyltransferase (NMT) is a promising antimalarial drug target. Despite biochemical similarities between Plasmodium vivax and human NMTs, our recent research demonstrated that high selectivity is achievable. Herein, we report PvNMT-inhibiting compounds aimed at identifying novel mechanisms of selectivity. Various functional groups are appended to a pyrazole moiety in the inhibitor to target a pocket formed beneath the peptide binding cleft. The inhibitor core group polarity, lipophilicity, and size are also varied to probe the water structure near a channel. Selectivity index values range from 0.8 to 125.3. Cocrystal structures of two selective compounds, determined at 1.97 and 2.43 Å, show that extensions bind the targeted pocket but with different stabilities. A bulky naphthalene moiety introduced into the core binds next to instead of displacing protein-bound waters, causing a shift in the inhibitor position and expanding the binding site. Our structure-activity data provide a conceptual foundation for guiding future inhibitor optimizations.

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