Exploring Subsite Selectivity within <i>Plasmodium vivax</i> <i>N</i>-Myristoyltransferase Using Pyrazole-Derived Inhibitors.

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.

SUBMITTER: Rodriguez-Hernandez D 

PROVIDER: S-EPMC11089503 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature