Division of Life Sciences, Division of Applied Life Science (BK21 Plus), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju, 52828, Republic of Korea.
College of Pharmacy, Inje University, 197 Inje-ro, Gimhae, Gyeongnam, 50834, Republic of Korea.
Comput Biol Chem. 2019 Dec;83:107113. doi: 10.1016/j.compbiolchem.2019.107113. Epub 2019 Sep 5.
Breast cancer is one of the major impediments affecting women globally. The ATP-dependant heat shock protein 90 (Hsp90) forms the central component of molecular chaperone machinery that predominantly governs the folding of newly synthesized peptides and their conformational maturation. It regulates the stability and function of numerous client proteins that are frequently upregulated and/or mutated in cancer cells, therefore, making Hsp90 inhibition a promising therapeutic strategy for the development of new efficacious drugs to treat breast cancer. In the present in silico investigation, a structure-based pharmacophore model was generated with hydrogen bond donor, hydrogen bond acceptor and hydrophobic features complementary to crucial residues Ala55, Lys58, Asp93, Ile96, Met98 and Thr184 directed at inhibiting the ATP-binding activity of Hsp90. Subsequently, the phytochemical dataset of 3210 natural compounds was screened to retrieve the prospective inhibitors after rigorous validation of the model pharmacophore. The retrieved 135 phytocompounds were further filtered by drug-likeness parameters including Lipinski's rule of five and ADMET properties, then investigated via molecular docking-based scoring. Molecular interactions were assessed using Genetic Optimisation for Ligand Docking program for 95 drug-like natural compounds against Hsp90 along with two clinical drugs as reference compounds - Geldanamycin and Radicicol. Docking studies revealed three phytochemicals are better than the investigated clinical drugs. The reference and hit compounds with dock scores of 48.27 (Geldanamycin), 40.90 (Radicicol), 73.04 (Hit1), 72.92 (Hit2) and 68.12 (Hit3) were further validated for their binding stability through molecular dynamics simulations. We propose that the non-macrocyclic scaffolds of three identified phytochemicals might aid in the development of novel therapeutic candidates against Hsp90-driven cancers.
乳腺癌是全球女性面临的主要障碍之一。ATP 依赖性热休克蛋白 90（Hsp90）是分子伴侣机制的核心组成部分，主要控制新合成肽的折叠及其构象成熟。它调节众多客户蛋白的稳定性和功能，这些蛋白在癌细胞中经常上调和/或突变，因此，抑制 Hsp90 成为开发新的有效治疗乳腺癌药物的有前途的治疗策略。在本计算机模拟研究中，基于结构的药效团模型生成，具有氢键供体、氢键受体和疏水性特征，与关键残基 Ala55、Lys58、Asp93、Ile96、Met98 和 Thr184 互补，旨在抑制 Hsp90 的 ATP 结合活性。随后，对 3210 种天然化合物的植物化学数据集进行筛选，以检索经过严格验证的模型药效团的潜在抑制剂。从检索到的 135 种植物化合物中，进一步通过药物相似性参数（包括 Lipinski 的五规则和 ADMET 特性）进行过滤，然后通过基于分子对接的评分进行研究。使用遗传优化配体对接程序对 95 种具有药物样性质的天然化合物和两种临床药物（geldanamycin 和 radicicol）与 Hsp90 进行分子相互作用评估。对接研究表明，三种植物化学物质优于研究中的临床药物。参考化合物和命中化合物的对接得分分别为 48.27（geldanamycin）、40.90（radicicol）、73.04（hit1）、72.92（hit2）和 68.12（hit3），通过分子动力学模拟进一步验证了它们的结合稳定性。我们提出，三种鉴定的植物化学物质的非大环骨架可能有助于开发针对 Hsp90 驱动的癌症的新型治疗候选物。
