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

Rodríguez-Hernández, Diego; Fenwick, Michael K.; Zigweid, Rachael; Sankaran, Banumathi; Myler, Peter J.; Sunnerhagen, Per; Kaushansky, Alexis; Staker, Bart L.; Grøtli, Morten

doi:10.1021/acs.jmedchem.4c00168

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

Journal Article · Mon Apr 29 00:00:00 EDT 2024 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.4c00168· OSTI ID:2447948

Rodríguez-Hernández, Diego ^[1]; ^[2]; Zigweid, Rachael ^[2]; Sankaran, Banumathi ^[3]; Myler, Peter J. ^[4]; ^[5]; ^[6]; ^[2]; ^[5]

Univ. of Gothenburg (Sweden); Univ. of Campinas (UNICAMP), Sao Paulo (Brazil)
Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, WA (United States); Seattle Children’s Research Institute, Seattle, WA (United States)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)
Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, WA (United States); Seattle Children’s Research Institute, Seattle, WA (United States); Univ. of Washington, Seattle, WA (United States)
Univ. of Gothenburg (Sweden)
Seattle Children’s Research Institute, Seattle, WA (United States); Univ. of Washington, Seattle, WA (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institute of General Medical Sciences (NIGMS)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2447948

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 9 Vol. 67; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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