几种与NK1受体结合的低分子量3,5-双三氟甲基苯衍生物

IF 0.4 4区 医学 Q4 PHARMACOLOGY & PHARMACY Acta poloniae pharmaceutica Pub Date : 2023-07-28 DOI:10.32383/appdr/163051
Piotr F. J. Lipiński, Joanna Matalińska
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引用次数: 0

摘要

我们感兴趣的是寻找最小的NK1受体(NK1R)配体。基于结构考虑和分子对接(评分),我们选择了6个简单的(低分子量,MW) 3,5-双三氟甲基苯衍生物,并测试了它们对人类NK1R的亲和力。结果表明,该化合物对受体具有可检测到的但非常低的亲和力(IC50 ~ 100 μM)。对接评分与实验亲和力之间的差异促使我们对AutoDock Vina评分功能对NK1R的性能进行了额外的测试。评分函数没有区分低mw -低亲和力和低mw -高亲和力的结合物,而与高mw -高亲和力的化合物相比,它低估了低mw -高亲和力的结合物的亲和力。评分函数在区分低毫瓦-低亲和度和低毫瓦-高亲和度粘结剂和诱饵集方面没有达到令人满意的性能。对其中一种化合物与NK1R的分子动力学模拟分析表明,对接可能高估了氢键相互作用的强度。
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NK1 receptor binding of a few low molecular weight 3,5-bistrifluoromethylbenzene derivatives
We were interested in finding smallest possible ligands of the NK1 receptor (NK1R). Based on structural considerations and molecular docking (scoring) we selected six simple (low molecular weight, MW) 3,5-bistrifluoromethylbenzene derivatives and tested them for human NK1R affinity. The compounds turned out to have detectable but very low affinity for the receptor (IC50 > 100 μM). The discrepancy between the docking scores and the experimental affinity provoked us to perform additional tests of AutoDock Vina scoring function performance against NK1R. The scoring function did not differentiate low MW-low affinity from low MW-high affinity binders, while it underestimated affinity of low MW-high affinity in comparison to high MW-high affinity compounds. The scoring function did not achieve satisfactory performance in discerning low MW-low affinity and low MW-high affinity binders from the sets of decoys. Analysis of molecular dynamics simulation of one of the studied compounds with NK1R suggests that docking might overestimate strength of the H-bond interaction.
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来源期刊
CiteScore
0.80
自引率
0.00%
发文量
74
审稿时长
6-12 weeks
期刊介绍: The international journal of the Polish Pharmaceutical Society is published in 6 issues a year. The journal offers Open Access publication of original research papers, short communications and reviews written in English, in all areas of pharmaceutical sciences. The following areas of pharmaceutical sciences are covered: Analysis, Biopharmacy, Drug Biochemistry, Drug Synthesis, Natural Drugs, Pharmaceutical Technology, Pharmacology and General. A bimonthly appearing in English since 1994, which continues “Acta Poloniae Pharmaceutica”, whose first issue appeared in December 1937. The war halted the activity of the journal’s creators. Issuance of “Acta Poloniae Pharmaceutica” was resumed in 1947. From 1947 the journal appeared irregularly, initially as a quarterly, then a bimonthly. In the years 1963 – 1973 alongside the Polish version appeared the English edition of the journal. Starting from 1974 only works in English are published in the journal. Since 1995 the journal has been appearing very regularly in two-month intervals (six books a year). The journal publishes original works from all fields of pharmacy, summaries of postdoctoral dissertations and laboratory notes.
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