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菲啶衍生物作为潜在的HIV-1蛋白酶抑制剂

Phenanthridine derivatives as potential HIV-1 protease inhibitors.

作者信息

Ershov Pavel V, Мezentsev Yuri V, Kaluzhskiy Leonid A, Ivanov Alexis S

机构信息

Federal State Budgetary Institution, V.N. Orekhovich Research Institute of Biomedical Chemistry, Moscow 119121, Russia.

Federal State Budgetary Institution, Centre for Strategic Planning and Management of Biomedical Health Risks of The Federal Medical Biological Agency, Moscow 119121, Russia.

出版信息

Biomed Rep. 2020 Dec;13(6):66. doi: 10.3892/br.2020.1373. Epub 2020 Oct 20.

Abstract

In the present study, the antiviral activity of phenanthridine derivatives was assessed. In total, the inhibitory effect of eight structurally similar low-molecular-weight hydrophobic compounds on HIV-1 protease (HIVp) was investigated. HIVp is a key enzyme in the HIV-1 life cycle. Surface plasmon resonance technology was used for affinity assessment of compounds binding with either monomeric or dimeric forms of HIVp. HIVp enzyme inhibition assays with chromogenic substrate VII were also used to determine the IC values. The most potent compound was 3,3,9,9-tetramethyl-3,4,9,10-tetrahydro-2H,8H-phenanthridine-1,7-dione which binds to monomeric and dimeric forms of HIVp (apparent dissociation constant, 2-7 µM; IC, 36 µМ), while possessing the most favorable Absorption, Distribution, Metabolism and Excretion parameters. Molecular docking simulations highlighted certain differences in the binding patterns of the phenanthridine derivatives with HIVp amino acid residues forming the flaps domain, monomer/monomer interfaces and the active site cavity of HIVp. Thus, it was hypothesized that the inhibitory effect of phenanthridine compounds on the enzymatic activity of HIVp may be due to restriction of substrate access to the HIVp active site.

摘要

在本研究中,评估了菲啶衍生物的抗病毒活性。总共研究了八种结构相似的低分子量疏水化合物对HIV-1蛋白酶(HIVp)的抑制作用。HIVp是HIV-1生命周期中的关键酶。表面等离子体共振技术用于评估化合物与HIVp单体或二聚体形式结合的亲和力。还使用含显色底物VII的HIVp酶抑制试验来确定IC值。最有效的化合物是3,3,9,9-四甲基-3,4,9,10-四氢-2H,8H-菲啶-1,7-二酮,它与HIVp的单体和二聚体形式结合(表观解离常数,2 - 7µM;IC,36µM),同时具有最有利的吸收、分布、代谢和排泄参数。分子对接模拟突出了菲啶衍生物与构成HIVp瓣结构域、单体/单体界面和HIVp活性位点腔的氨基酸残基的结合模式存在某些差异。因此,推测菲啶化合物对HIVp酶活性的抑制作用可能是由于底物进入HIVp活性位点受到限制。

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