TEM β-内酰胺酶变构位点与相应先导药物的研究

目的 对前期研究发现的TEM β-内酰胺酶变构位点的功能性进行进一步的验证，并针对该位点开展潜在的先导药物分子的研究。方法 采用长时间全原子分子动力学模拟，分别对β-内酰胺酶的野生型结构与耐药性突变型进行模拟，通过分析活性位点和变构位点在野生型与突变型中功能性变化的情况，以研究变构活性位点是否可以克服抗生素的耐药性；并针对变构位点采用虚拟筛选的方法，通过筛选大型化合物数据库，筛选潜在的先导候选药物分子。结果与结论 长时间分子动力学模拟表明，不同于活性位点，β-内酰胺酶变构活性位点不会受到突变体的影响；虚拟筛选发现一些苯基呋喃类和吲哚类化合物可结合于变构位点，具有潜在的变构抑制调节功能。本文再次验证了前期发现的TEM β-内酰胺酶变构位点潜在的成药性，并针对该位点发现了两大类候选变构抑制剂。

TEM β-lactamase allosteric sites and corresponding lead compounds

Objective Based on our previous identification of allosteric binding site for anti-drug resistance, functionality of the allosteric site was further validated in this work. Meanwhile, lead identification of allosteric modulators was performed. Methods To study whether the identified allosteric site can overcome the drug resistance as expected, long-time all-atom molecular dynamics simulations were performed. Then the relationship between functions and conformational changes of allosteric site and active site were monitored. Finally, virtual screening was performed to discover potential lead allosteric modulators. Results and Conclusion The molecular dynamics simulations revealed that the function of identified allosteric site of β-lactamase is not affected by the mutations of β-lactamase. In other words, it can potentially overcome the drug resistance. Two groups of compounds, i.e., furans and indoles, were identified as potential lead allosteric modulators. This work further validated the functionality of the identified allosteric site, and two groups of compounds were discovered as candidate allosteric modulators.