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类似洛那法尼化合物的发现：药效团建模与分子动力学研究。

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

作者信息

Rampogu Shailima, Baek Ayoung, Son Minky, Park Chanin, Yoon Sanghwa, Parate Shraddha, Lee Keun Woo

机构信息

Division of Life Science, 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.

出版信息

ACS Omega. 2020 Jan 22;5(4):1773-1781. doi: 10.1021/acsomega.9b02263. eCollection 2020 Feb 4.

DOI:10.1021/acsomega.9b02263
PMID:32039312
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7003205/
Abstract

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.

摘要

早衰症是一种全球关注的罕见遗传疾病，表现为过早衰老且没有有效治疗方法。在这种情况下，法尼基转移酶抑制剂（FTIs）被视为有前景的候选药物。相应地，利用洛那法尼的特征生成了一个药效团模型。所选的药效团模型用于筛选InterBioScreen天然化合物数据库，以检索潜在的先导候选物。应用了一系列筛选步骤来评估化合物的类药性。将获得的化合物使用Discovery Studio（DS）提供的CDOCKER模块进行分子对接。随后，与参考化合物相比，有三种化合物（命中物）显示出更高的对接分数，并通过稳定的分子动力学模拟结果证明了关键残基相互作用。综上所述，我们因此提出三种已鉴定的命中物作为FTIs，它们可能进一步作为设计新化合物的化学空间。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89c0/7003205/585e004f1a82/ao9b02263_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89c0/7003205/8f03ba09aa77/ao9b02263_0008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89c0/7003205/b544cd2fdd52/ao9b02263_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89c0/7003205/585e004f1a82/ao9b02263_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89c0/7003205/8f03ba09aa77/ao9b02263_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89c0/7003205/c5c5a1d414da/ao9b02263_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89c0/7003205/a1d175ce51e8/ao9b02263_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89c0/7003205/6d1faaeaeb0d/ao9b02263_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89c0/7003205/2aba0ae6ffd0/ao9b02263_0005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89c0/7003205/585e004f1a82/ao9b02263_0001.jpg

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