Grup de Recerca en Nutrigenòmica, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Campus de Sescelades, Tarragona, Catalonia, Spain.
PLoS One. 2011 Feb 24;6(2):e16903. doi: 10.1371/journal.pone.0016903.
Their large scaffold diversity and properties, such as structural complexity and drug similarity, form the basis of claims that natural products are ideal starting points for drug design and development. Consequently, there has been great interest in determining whether such molecules show biological activity toward protein targets of pharmacological relevance. One target of particular interest is hIKK-2, a serine-threonine protein kinase belonging to the IKK complex that is the primary component responsible for activating NF-κB in response to various inflammatory stimuli. Indeed, this has led to the development of synthetic ATP-competitive inhibitors for hIKK-2. Therefore, the main goals of this study were (a) to use virtual screening to identify potential hIKK-2 inhibitors of natural origin that compete with ATP and (b) to evaluate the reliability of our virtual-screening protocol by experimentally testing the in vitro activity of selected natural-product hits.
METHODOLOGY/PRINCIPAL FINDINGS: We thus predicted that 1,061 out of the 89,425 natural products present in the studied database would inhibit hIKK-2 with good ADMET properties. Notably, when these 1,061 molecules were merged with the 98 synthetic hIKK-2 inhibitors used in this study and the resulting set was classified into ten clusters according to chemical similarity, there were three clusters that contained only natural products. Five molecules from these three clusters (for which no anti-inflammatory activity has been previously described) were then selected for in vitro activity testing, in which three out of the five molecules were shown to inhibit hIKK-2.
CONCLUSIONS/SIGNIFICANCE: We demonstrated that our virtual-screening protocol was successful in identifying lead compounds for developing new inhibitors for hIKK-2, a target of great interest in medicinal chemistry. Additionally, all the tools developed during the current study (i.e., the homology model for the hIKK-2 kinase domain and the pharmacophore) will be made available to interested readers upon request.
天然产物具有丰富的支架多样性和特性，例如结构复杂性和药物相似性，这为天然产物是药物设计和开发的理想起点提供了依据。因此，人们非常关注这些分子是否对具有药理学意义的蛋白质靶标表现出生物活性。一个特别感兴趣的靶标是 hIKK-2，它是一种丝氨酸-苏氨酸蛋白激酶，属于 IKK 复合物，是对各种炎症刺激激活 NF-κB 的主要成分。事实上，这导致了合成 ATP 竞争性抑制剂用于 hIKK-2 的开发。因此，本研究的主要目标是 (a) 使用虚拟筛选来识别与 ATP 竞争的天然来源的潜在 hIKK-2 抑制剂，以及 (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。
方法/主要发现：因此，我们预测在研究数据库中存在的 89425 种天然产物中有 1061 种会以良好的 ADMET 特性抑制 hIKK-2。值得注意的是，当将这 1061 种分子与本研究中使用的 98 种合成 hIKK-2 抑制剂合并，并根据化学相似性将合并后的集合分为十个簇时，有三个簇只包含天然产物。从这三个簇中选择了五个分子（以前没有描述过它们的抗炎活性）进行体外活性测试，其中三个分子被证明抑制了 hIKK-2。
结论/意义：我们证明了我们的虚拟筛选方案成功地识别了开发 hIKK-2 新抑制剂的先导化合物，hIKK-2 是药物化学中非常感兴趣的靶标。此外，当前研究中开发的所有工具（即 hIKK-2 激酶结构域的同源模型和药效团）将根据需要提供给感兴趣的读者。
