Department of Pharmacology, University of California at San Diego, La Jolla, CA, USA.
Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA, USA.
Chem Biol Drug Des. 2018 Jun;91(6):1068-1077. doi: 10.1111/cbdd.13170. Epub 2018 Feb 4.
Malaria, mainly caused by Plasmodium falciparum and Plasmodium vivax, has been a growing cause of morbidity and mortality. P. falciparum is more lethal than is P. vivax, but there is a vital need for effective drugs against both species. Geranylgeranyl diphosphate synthase (GGPPS) is an enzyme involved in the biosynthesis of quinones and in protein prenylation and has been proposed to be a malaria drug target. However, the structure of P. falciparumGGPPS (PfGGPPS) has not been determined, due to difficulties in crystallization. Here, we created a PfGGPPS model using the homologous P.vivaxGGPPS X-ray structure as a template. We simulated the modeled PfGGPPS as well as PvGGPPS using conventional and Gaussian accelerated molecular dynamics in both apo- and GGPP-bound states. The MD simulations revealed a striking similarity in the dynamics of both enzymes with loop 9-10 controlling access to the active site. We also found that GGPP stabilizes PfGGPPS and PvGGPPS into closed conformations and via similar mechanisms. Shape-based analysis of the binding sites throughout the simulations suggests that the two enzymes will be readily targeted by the same inhibitors. Finally, we produced three MD-validated conformations of PfGGPPS to be used in future virtual screenings for potential new antimalarial drugs acting on both PvGGPPS and PfGGPPS.
疟疾主要由恶性疟原虫和间日疟原虫引起，已成为发病率和死亡率不断上升的原因。恶性疟原虫比间日疟原虫更致命，但迫切需要针对这两种疟原虫的有效药物。香叶基香叶基二磷酸合酶（GGPPS）是一种参与醌类生物合成和蛋白质异戊烯化的酶，已被提议作为抗疟药物靶点。然而，由于结晶困难，恶性疟原虫 GGPPS（PfGGPPS）的结构尚未确定。在这里，我们使用同源的间日疟原虫 GGPPS X 射线结构作为模板创建了 PfGGPPS 模型。我们模拟了建模的 PfGGPPS 以及 PvGGPPS，使用常规和高斯加速分子动力学，分别在 apo 和 GGPP 结合状态下。MD 模拟显示，两种酶的动力学非常相似，Loop 9-10 控制着进入活性位点的通道。我们还发现，GGPP 使 PfGGPPS 和 PvGGPPS 稳定为封闭构象，并通过类似的机制。在整个模拟过程中对结合位点的形状分析表明，两种酶将很容易被相同的抑制剂靶向。最后，我们生成了 PfGGPPS 的三个 MD 验证构象，用于未来针对同时作用于 PvGGPPS 和 PfGGPPS 的潜在新抗疟药物的虚拟筛选。
