Zaki Magdi E A, Al-Hussain Sami A, Bukhari Syed Nasir Abbas, Masand Vijay H, Rathore Mithilesh M, Thakur Sumer D, Patil Vaishali M
Department of Chemistry, Faculty of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh 13318, Saudi Arabia.
Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Al Jouf 72388, Saudi Arabia.
Pharmaceuticals (Basel). 2022 Mar 1;15(3):303. doi: 10.3390/ph15030303.
Cancer is a major life-threatening disease with a high mortality rate in many countries. Even though different therapies and options are available, patients generally prefer chemotherapy. However, serious side effects of anti-cancer drugs compel us to search for a safer drug. To achieve this target, Hsp90 (heat shock protein 90), which is responsible for stabilization of many oncoproteins in cancer cells, is a promising target for developing an anti-cancer drug. The QSAR (Quantitative Structure-Activity Relationship) could be useful to identify crucial pharmacophoric features to develop a Hsp90 inhibitor. Therefore, in the present work, a larger dataset encompassing 1141 diverse compounds was used to develop a multi-linear QSAR model with a balance of acceptable predictive ability (Predictive QSAR) and mechanistic interpretation (Mechanistic QSAR). The new developed six-parameter model satisfies the recommended values for a good number of validation parameters such as R2tr = 0.78, Q2LMO = 0.77, R2ex = 0.78, and CCCex = 0.88. The present analysis reveals that the Hsp90 inhibitory activity is correlated with different types of nitrogen atoms and other hidden structural features such as the presence of hydrophobic ring/aromatic carbon atoms within a specific distance from the center of mass of the molecule, etc. Thus, the model successfully identified a variety of reported as well as novel pharmacophoric features. The results of QSAR analysis are further vindicated by reported crystal structures of compounds with Hsp90.
癌症是一种主要的危及生命的疾病，在许多国家死亡率很高。尽管有不同的治疗方法和选择，但患者通常更喜欢化疗。然而，抗癌药物的严重副作用促使我们寻找更安全的药物。为了实现这一目标，热休克蛋白90（Hsp90），它负责癌细胞中许多癌蛋白的稳定，是开发抗癌药物的一个有前景的靶点。定量构效关系（QSAR）对于识别开发Hsp90抑制剂的关键药效特征可能有用。因此，在本研究中，使用了一个包含1141种不同化合物的更大数据集来开发一个多线性QSAR模型，该模型在可接受的预测能力（预测QSAR）和机理解释（机理QSAR）之间取得平衡。新开发的六参数模型满足了许多验证参数的推荐值，如R2tr = 0.78、Q2LMO = 0.77、R2ex = 0.78和CCCex = 0.88。目前的分析表明，Hsp90抑制活性与不同类型的氮原子以及其他隐藏的结构特征相关，例如在距分子质心特定距离内存在疏水环/芳香碳原子等。因此，该模型成功地识别了各种已报道的以及新的药效特征。QSAR分析的结果通过报道的与Hsp90结合的化合物晶体结构得到了进一步证实。
