Discovery of Lonafarnib-Like Compounds: Pharmacophore Modeling and Molecular Dynamics Studies.,ACS Omega

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Discovery of Lonafarnib-Like Compounds: Pharmacophore Modeling and Molecular Dynamics Studies.
ACS Omega ( IF 3.7 ) Pub Date : 2020-01-22 , DOI: 10.1021/acsomega.9b02263
Shailima Rampogu ₁ , Ayoung Baek ₁ , Minky Son ₁ , Chanin Park ₁ , Sanghwa Yoon ₁ , Shraddha Parate ₁ , Keun Woo Lee ₁

Affiliation

Progeria is a globally noticed rare genetic disorder manifested by premature aging with no effective treatment. Under these circumstances, farnesyltransferase inhibitors (FTIs) are marked as promising drug candidates. Correspondingly, a pharmacophore model was generated exploiting the features of lonafarnib. The selected pharmacophore model was allowed to screen the InterBioScreen natural compound database to retrieve the potential lead candidates. A series of filtering steps were applied to assess the drug-likeness of the compounds. The obtained compounds were advanced to molecular docking employing the CDOCKER module available with Discovery Studio (DS). Subsequently, three compounds (Hits) have displayed a higher dock score and demonstrated key residue interactions with stable molecular dynamics simulation results compared to the reference compound. Taken together, we therefore put forth three identified Hits as FTIs that may further serve as chemical spaces in designing new compounds.

中文翻译：

Lonafarnib 类化合物的发现：药效团建模和分子动力学研究。

早衰症是一种全球关注的罕见遗传性疾病，表现为过早衰老且没有有效的治疗方法。在这种情况下，法尼基转移酶抑制剂（FTI）被认为是有前途的候选药物。相应地，利用lonafarnib的特征生成了药效团模型。选定的药效团模型可用于筛选 InterBioScreen 天然化合物数据库，以检索潜在的先导候选物。应用一系列过滤步骤来评估化合物的药物相似性。使用 Discovery Studio (DS) 提供的 CDOCKER 模块将获得的化合物进行分子对接。随后，与参考化合物相比，三种化合物 (Hits) 显示出更高的停靠分数，并展示了关键残基相互作用和稳定的分子动力学模拟结果。因此，综上所述，我们提出了三个已确定的命中作为 FTI，它们可以进一步用作设计新化合物的化学空间。

更新日期：2020-02-04

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