Data from: Computational design of protein-based inhibitors of Plasmodium vivax subtilisin-like 1 protease

Background: Malaria remains a major global health concern. The development of novel therapeutic strategies is critical to overcome the selection of multiresistant parasites. The subtilisin-like protease (SUB1) involved in the egress of daughter Plasmodium parasites from infected erythrocytes and in their subsequent invasion into fresh erythrocytes has emerged as an interesting new drug target. Findings: Using a computational approach based on homology modeling, protein–protein docking and mutation scoring, we designed protein–based inhibitors of Plasmodium vivax SUB1 (PvSUB1) and experimentally evaluated their inhibitory activity. The small peptidic trypsin inhibitor EETI-II was used as scaffold. We mutated residues at specific positions (P4 and P1) and calculated the change in free-energy of binding with PvSUB1. In agreement with our predictions, we identified a mutant of EETI-II (EETI-II-P4LP1W) with a Ki in the medium micromolar range. Conclusions: Despite the challenges related to the lack of an experimental structure of PvSUB1, the computational protocol we developed in this study led to the design of protein-based inhibitors of PvSUB1. The approach we describe in this paper, together with other examples, demonstrates the capabilities of computational procedures to accelerate and guide the design of novel proteins with interesting therapeutic applications.

研究背景：疟疾仍是全球性重大公共卫生难题。开发新型治疗策略对于克服多抗性疟原虫的筛选扩散至关重要。类枯草杆菌蛋白酶（subtilisin-like protease, SUB1）可介导子代疟原虫从受感染红细胞中逸出，并随后入侵新鲜红细胞，现已成为颇具潜力的新型药物靶点。
研究结果：本研究采用基于同源建模、蛋白质-蛋白质对接及突变评分的计算方法，设计了间日疟原虫SUB1（Plasmodium vivax SUB1, PvSUB1）的蛋白类抑制剂，并对其抑制活性开展了实验评估。我们以小型肽类胰蛋白酶抑制剂EETI-II作为骨架载体，对其特定位置（P4与P1位）的氨基酸残基进行突变，并计算了其与PvSUB1结合的自由能变化。与预测结果一致，我们筛选得到EETI-II的突变体EETI-II-P4LP1W，其抑制常数Ki处于中等微摩尔浓度范围。
研究结论：尽管面临缺乏PvSUB1实验结构的挑战，本研究开发的计算流程仍成功设计出PvSUB1的蛋白类抑制剂。本研究所述方法结合其他相关案例，证明了计算流程能够加速并指导具有潜在治疗应用价值的新型蛋白的设计开发。