Grup de Recerca en Nutrigenòmica, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Campus de Sescelades, Tarragona, Catalonia, Spain.
PLoS One. 2012;7(9):e44971. doi: 10.1371/journal.pone.0044971. Epub 2012 Sep 12.
There has been great interest in determining whether natural products show biological activity toward protein targets of pharmacological relevance. One target of particular interest is DPP-IV whose most important substrates are incretins that, among other beneficial effects, stimulates insulin biosynthesis and secretion. Incretins have very short half-lives because of their rapid degradation by DPP-IV and, therefore, inhibiting this enzyme improves glucose homeostasis. As a result, DPP-IV inhibitors are of considerable interest to the pharmaceutical industry. The main goals of this study were (a) to develop a virtual screening process to identify potential DPP-IV inhibitors of natural origin; (b) to evaluate the reliability of our virtual-screening protocol by experimentally testing the in vitro activity of selected natural-product hits; and (c) to use the most active hit for predicting derivatives with higher binding affinities for the DPP-IV binding site.
METHODOLOGY/PRINCIPAL FINDINGS: We predicted that 446 out of the 89,165 molecules present in the natural products subset of the ZINC database would inhibit DPP-IV with good ADMET properties. Notably, when these 446 molecules were merged with 2,342 known DPP-IV inhibitors and the resulting set was classified into 50 clusters according to chemical similarity, there were 12 clusters that contained only natural products for which no DPP-IV inhibitory activity has been previously reported. Nine molecules from 7 of these 12 clusters were then selected for in vitro activity testing and 7 out of the 9 molecules were shown to inhibit DPP-IV (where the remaining two molecules could not be solubilized, preventing the evaluation of their DPP-IV inhibitory activity). Then, the hit with the highest activity was used as a lead compound in the prediction of more potent derivatives.
CONCLUSIONS/SIGNIFICANCE: We have demonstrated that our virtual-screening protocol was successful in identifying novel lead compounds for developing more potent DPP-IV inhibitors.
人们一直热衷于确定天然产物是否对具有药理相关性的蛋白质靶标具有生物活性。一个特别感兴趣的靶标是 DPP-IV，其最重要的底物是肠降血糖素，除了其他有益作用外，还能刺激胰岛素的生物合成和分泌。肠降血糖素由于被 DPP-IV 迅速降解，半衰期非常短，因此抑制这种酶可以改善葡萄糖内稳态。因此，DPP-IV 抑制剂受到制药行业的极大关注。本研究的主要目标是：(a) 开发一种虚拟筛选过程，以鉴定具有天然来源的潜在 DPP-IV 抑制剂；(b) 通过实验测试所选天然产物命中物的体外活性来评估我们虚拟筛选方案的可靠性；(c) 使用最活跃的命中物来预测与 DPP-IV 结合位点具有更高结合亲和力的衍生物。
方法/主要发现：我们预测，ZINC 数据库天然产物子集中的 89165 种分子中的 446 种将具有良好的 ADMET 特性，从而抑制 DPP-IV。值得注意的是，当将这 446 种分子与 2342 种已知的 DPP-IV 抑制剂合并，并根据化学相似性将所得集合分为 50 个簇时，有 12 个簇仅包含先前未报道过 DPP-IV 抑制活性的天然产物。然后从这 12 个簇中的 7 个簇中选择 9 种分子进行体外活性测试，其中 7 种分子被证明抑制 DPP-IV（其余 2 种分子不能溶解，从而无法评估其 DPP-IV 抑制活性）。然后，使用活性最高的命中物作为先导化合物来预测更有效的衍生物。
结论/意义：我们已经证明，我们的虚拟筛选方案成功地鉴定了新型先导化合物，用于开发更有效的 DPP-IV 抑制剂。
