Abstract

There has recently been interest in the development of small-molecule inhibitors of the oligomerization of Bacillus anthracis protective antigen for therapeutic use. Some of the proposed lead compounds have, however, unfavorable solubility in aqueous medium, which prevents their clinical use. In this computational work, we have designed several hundreds of derivatives with progressively higher hydro-solubility and tested their ability to dock the relevant binding cavity. The highest-ranking docking hits were then subjected to 125 ns-long simulations to ascertain the stability of the binding modes. Several of the potential candidates performed quite disappointingly, but two molecules showed very stable binding modes throughout the complete simulations. Besides the identification of these two promising leads, these molecular dynamics simulations allowed the discovery of several insights that shall prove useful in the further improvement of these candidates toward higher potency and stability.

Communicated by Ramaswamy H. Sarma

摘要

最近人们对开发炭疽芽孢杆菌寡聚化的小分子抑制剂感兴趣用于治疗用途的保护性抗原。然而，一些提议的先导化合物在水性介质中具有不利的溶解性，这阻碍了它们的临床应用。在这项计算工作中，我们设计了数百种水溶性逐渐提高的衍生物，并测试了它们对接相关结合腔的能力。然后对排名最高的对接命中进行 125 ns 长的模拟，以确定结合模式的稳定性。几个潜在的候选者表现得相当令人失望，但在整个模拟过程中，两个分子表现出非常稳定的结合模式。除了确定这两个有前途的线索，

由 Ramaswamy H. Sarma 交流