Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal, PIN 741235, India.
Curr Drug Metab. 2022;23(7):521-537. doi: 10.2174/1389200223666220718161754.
Aflatoxin B1 is a harmful hepatocarcinogen which is metabolized in our body by Cytochrome P450 enzymes, namely CYP1A2, CYP3A4, CYP3A5, and CYP3A7, into toxic (exo-8, 9-epoxide) and nontoxic (AFQ1, endo-epoxide) products. We have found from the literature that due to cooperativity, the rate of metabolic reactions increases in CYP1A2 and CYP3A4 involving more than one site of proteins to form two products at a given time, whereas the interaction of CYP3A5 and CYP3A7 is still unknown. Our work aims to study these four enzymes with AFB1 based on binding site pocket characterization and to find the probable resultant products at each binding site.
We used computational approaches like homology modeling, molecular docking to form mono and double ligated systems, molecular dynamic simulations to analyze the potential energies (vdW & electrostatic), PCA, RMSF, and residue-wise interactions at the active as well as allosteric sites of these four enzymes.
We found that CYP1A2, CYP3A4, and CYP3A5 were more hydrophobic at the first site and may induce epoxidation reaction to form toxic products, whereas the second site would be expected to be more polar and comprising charged interactions, thus enhancing non-toxic hydroxylated products. However, in CYP3A7, the first site favors hydroxylation, whereas the second site is involved in higher hydrophobic interactions.
Thus, in the fetus where AFB1 is metabolized only by CYP3A7, a lower concentration of toxic metabolites will be expected, while in adults exhibiting CYP1A2, CYP3A4 and CYP3A5 may increase the concentration of the toxic metabolites due to the combined effect of these enzymes, consequently increasing liver toxicity. We believe that AFB1 binding characteristics will be helpful for medicinal chemists in the process of designing a new drug.
黄曲霉毒素 B1 是一种有害的肝癌致癌物，在我们体内被细胞色素 P450 酶（即 CYP1A2、CYP3A4、CYP3A5 和 CYP3A7）代谢为有毒（外-8、9-环氧化物）和无毒（AFQ1、内-环氧化物）产物。我们从文献中发现，由于协同作用，涉及蛋白质多个位点的 CYP1A2 和 CYP3A4 代谢反应速率增加，在给定时间形成两种产物，而 CYP3A5 和 CYP3A7 的相互作用仍不清楚。我们的工作旨在基于结合口袋特征研究这四种酶与 AFB1 的相互作用，并找到每个结合位点可能的产物。
我们使用同源建模、分子对接等计算方法形成单键和双键体系，分子动力学模拟分析这些四种酶的活性和别构位点的潜在能量（vdW 和静电）、PCA、RMSF 和残基相互作用。
我们发现 CYP1A2、CYP3A4 和 CYP3A5 在第一个位点更具疏水性，可能诱导环氧化反应形成有毒产物，而第二个位点预计更具极性并包含带电相互作用，从而增强无毒的羟基化产物。然而，在 CYP3A7 中，第一个位点有利于羟基化，而第二个位点涉及更高的疏水性相互作用。
因此，在仅由 CYP3A7 代谢 AFB1 的胎儿中，预计有毒代谢物的浓度会较低，而在表现出 CYP1A2、CYP3A4 和 CYP3A5 的成年人中，由于这些酶的联合作用，有毒代谢物的浓度可能会增加，从而增加肝脏毒性。我们相信 AFB1 的结合特征将有助于药物化学家在新药设计过程中。
