In silico and in vitro studies on interaction of novel non-imidazole histamine H3R antagonists with CYP3A4.,Bioorganic & Medicinal Chemistry Letters

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In silico and in vitro studies on interaction of novel non-imidazole histamine H3R antagonists with CYP3A4.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-03-29 , DOI: 10.1016/j.bmcl.2020.127147
Sabina Podlewska ₁ , Gniewomir Latacz ₂ , Dorota Łażewska ₂ , Katarzyna Kieć-Kononowicz ₂ , Jadwiga Handzlik ₂

Affiliation

The paper presents in silico study to explain differences in the influence of the series of non-imidazole histamine receptor H3 ligands on the activity of cytochrome P-450 3A4 isoform, which was verified in in vitro tests. The compounds appeared to induce broad range of effects - from significant inhibition (-61% reduction of CYP3A4 control activity) to extreme activation (+713% of control activity). Structure-activity relationship for examined compounds was analyzed, with special attention paid to the influence of substituent and the chain length. Docking, molecular dynamics studies, and their statistical analysis allowed to identify those interactions that can be responsible for determination of particular activity type of a compound toward CYP3A4 (activation/inhibition). It resulted in indication of several amino acid residues, which should be carefully analyzed during estimation of compound effects on CYP3A4 activity.

中文翻译：

新型非咪唑组胺H3R拮抗剂与CYP3A4相互作用的计算机和体外研究。

本文介绍了计算机研究，以解释一系列非咪唑组胺受体H3配体对细胞色素P-450 3A4同工型活性的影响的差异，这已在体外测试中得到验证。这些化合物似乎引起广泛的作用-从显着抑制（CYP3A4控制活性降低-61％）到极端激活（控制活性+ 713％）。分析了所检查化合物的构效关系，并特别注意取代基和链长的影响。通过对接，分子动力学研究及其统计分析，可以识别可能导致确定化合物对CYP3A4特定活性类型（激活/抑制）的相互作用。结果表明有几个氨基酸残基，

更新日期：2020-04-20

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