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Current Drug Metabolism

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ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

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Research Article

Comparative Study of Binding Pockets in Human CYP1A2, CYP3A4, CYP3A5, and CYP3A7 with Aflatoxin B1, a Hepato-Carcinogen, by Molecular Dynamics Simulation & Principal Component Analysis

Author(s): Nikhat Saba and Alpana Seal*

Volume 23, Issue 7, 2022

Published on: 23 August, 2022

Page: [521 - 537] Pages: 17

DOI: 10.2174/1389200223666220718161754

Price: $65

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Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Cytochrome P450 1A2, 3A4, 3A5 and 3A7, aflatoxin B1, metabolism, liver cancer, AFB1-8, 9-epoxide, hydroxylation, docking, molecular dynamic simulation, principal component analysis.

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