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.

中文翻译：

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使用吡唑衍生抑制剂探索间日疟原虫 N-肉豆蔻酰转移酶内的亚位点选择性

N-肉豆蔻酰转移酶（NMT）是一个有前途的抗疟药物靶点。尽管间日疟原虫和人类 NMT之间的生化相似，但我们最近的研究表明，高选择性是可以实现的。在此，我们报告了Pv NMT 抑制化合物，旨在确定新的选择性机制。抑制剂中的吡唑部分附加了各种官能团，以靶向肽结合裂口下方形成的口袋。抑制剂核心基团的极性、亲脂性和大小也发生变化，以探测通道附近的水结构。选择性指数值范围为 0.8 至 125.3。两种选择性化合物的共晶结构（在 1.97 和 2.43 Å 处测定）表明，延伸部分结合了目标口袋，但具有不同的稳定性。引入核心的大萘部分与蛋白质结合水结合，而不是取代蛋白质结合水，导致抑制剂位置发生变化并扩大结合位点。我们的结构-活性数据为指导未来抑制剂优化提供了概念基础。