Department of Chemical Technology of Drugs, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznań, Poland.
Department of Inorganic and Analytical Chemistry, Nicolaus Copernicus University, Collegium Medicum, Dr. A. Jurasza 2, 85-089 Bydgoszcz, Poland.
Int J Mol Sci. 2023 Jul 14;24(14):11481. doi: 10.3390/ijms241411481.
Cytochromes CYP1A1, CYP1A2, and CYP1B1, the members of the cytochrome P450 family 1, catalyze the metabolism of endogenous compounds, drugs, and non-drug xenobiotics which include substances involved in the process of carcinogenesis, cancer chemoprevention, and therapy. In the present study, the interactions of three selected polymethoxy-trans-stilbenes, analogs of a bioactive polyphenol trans-resveratrol (3,5,4'-trihydroxy-trans-stilbene) with the binding sites of CYP1 isozymes were investigated with molecular dynamics (MD) simulations. The most pronounced structural changes in the CYP1 binding sites were observed in two substrate recognition sites (SRS): SRS2 (helix F) and SRS3 (helix G). MD simulations show that the number and position of water molecules occurring in CYP1 APO and in the structures complexed with ligands are diverse. The presence of water in binding sites results in the formation of water-protein, water-ligand, and bridging ligand-water-protein hydrogen bonds. Analysis of the solvent and substrate channels opening during the MD simulation showed significant differences between cytochromes in relation to the solvent channel and the substrate channels 2c, 2ac, and 2f. The results of this investigation lead to a deeper understanding of the molecular processes that occur in the CYP1 binding sites and may be useful for further molecular studies of CYP1 functions.
细胞色素 CYP1A1、CYP1A2 和 CYP1B1 是细胞色素 P450 家族 1 的成员，可催化内源性化合物、药物和非药物外源性物质的代谢，这些物质包括参与致癌过程、癌症化学预防和治疗的物质。在本研究中，使用分子动力学 (MD) 模拟研究了三种选定的多甲氧基反式-二苯乙烯（生物活性多酚反式白藜芦醇（3,5,4'-三羟基反式-二苯乙烯）的类似物）与 CYP1 同工酶结合位点的相互作用。在两个底物识别位点 (SRS)：SRS2（F 螺旋）和 SRS3（G 螺旋）中观察到 CYP1 结合位点的结构变化最为明显。MD 模拟表明，在 CYP1 APO 和与配体结合的结构中出现的水分子的数量和位置是多种多样的。结合位点中水分子的存在导致形成水-蛋白、水-配体和桥接配体-水-蛋白氢键。在 MD 模拟过程中对溶剂和底物通道打开的分析表明，在溶剂通道和底物通道 2c、2ac 和 2f 方面，细胞色素之间存在显著差异。这项研究的结果使我们更深入地了解发生在 CYP1 结合位点的分子过程，并且可能有助于进一步研究 CYP1 功能的分子研究。
