Design of antimalarial transmission blocking agents: Pharmacophore mapping of ligands active against stage-V mature gametocytes of <i>Plasmodium falciparum</i>

The discovery of transmission-blocking (T-B) agents is crucial for preventing and complete removal of malaria infection. However, most of the existing antimalarials are only active against the asexual stages of <i>Plasmodium</i> parasite, but ineffective against the sexual stage (gametocytes). In this background, we have developed pharmacophore models against the stage-V mature gametocytes of <i>P. falciparum</i> parasites. The pharmacophore model (Hypo-1) showed five pharmacophoric features namely, one hydrogen bond donor (HBD), one hydrophobic aliphatic (HYAl), one ring aromatic (RA), and two hydrophobic aromatic (HYAr) essential for the anti-gametocytic activity. The amino, methyl, fused phenyl ring of the quinazoline heterocycle, two phenyl rings of biphenyl moiety (HBD, HYAl, HYAr1, HYAr2 and RA) are the crucial features responsible for the non-specific anti-gametocytic activity (PfG). Subsequently, the model (Hypo-2) developed against the stage-V female gametocytes (PffG) showed the contribution of three pharmacophoric features namely, two hydrogen bond acceptor (HYA) and one RA required for the anti-gametocytic activity. The sulfhydryl, imine and pyridyl groups are observed to be essential for anti-gametocytic activity against female gametocytes. Both the models (PfG and PfGG) showed the classification accuracies of 78.26 and 71.64% for training set compounds and 60.80 and 60.18% for the test set compounds, respectively, for classification of compounds into higher and lower active classes. Also, both the models were found to retain the higher active compounds (IC₅₀ &lt;100 nM) in top 1% of total compounds (actives and decoys) as observed after screening the decoy set compounds. Communicated by Ramaswamy H Sarma传播阻断（transmission-blocking, T-B）制剂的发现对于预防并彻底清除疟疾感染至关重要。然而，现有抗疟药物大多仅对疟原虫（Plasmodium）的无性生殖阶段具有活性，却对其有性生殖阶段（配子体）无效。在此背景下，本研究针对恶性疟原虫（P. falciparum）第V期成熟配子体构建了药效团模型。其中，Hypo-1模型包含5个药效团特征：1个氢键供体（hydrogen bond donor, HBD）、1个脂肪族疏水基团（hydrophobic aliphatic, HYAl）、1个芳香环基团（ring aromatic, RA）以及2个芳香族疏水基团（hydrophobic aromatic, HYAr），这些特征是抗配子体活性所必需的。喹唑啉杂环的氨基、甲基、稠合苯环，以及联苯基团的两个苯环（对应HBD、HYAl、HYAr1、HYAr2与RA），正是介导非特异性抗配子体活性（PfG）的关键特征。随后，针对第V期雌性配子体（PffG）构建的Hypo-2模型则包含3个药效团特征：2个氢键受体（hydrogen bond acceptor, HYA）与1个芳香环基团（RA），这些特征是抗配子体活性所必需的。研究发现，巯基、亚胺与吡啶基团是针对雌性配子体发挥抗配子体活性的必需基团。在将化合物划分为高活性与低活性类别的分类任务中，两款模型（PfG与PfGG）对训练集化合物的分类准确率分别为78.26%与71.64%，对测试集化合物的分类准确率则分别为60.80%与60.18%。此外，通过诱饵化合物集筛选后发现，两款模型均能将半最大抑制浓度（IC₅₀ < 100 nM）的高活性化合物富集于总化合物（活性化合物与诱饵化合物）前1%的范围内。本文由Ramaswamy H Sarma提交。