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In Silico Prediction of the Metabolic Resistance of Vitamin D Analogs against CYP3A4 Metabolizing Enzyme. | LitMetric

In Silico Prediction of the Metabolic Resistance of Vitamin D Analogs against CYP3A4 Metabolizing Enzyme.

Int J Mol Sci

Department of Bioanalysis and Drug Analysis, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha, 02-097 Warsaw, Poland.

Published: July 2022

AI Article Synopsis

  • Both CYP3A4 and CYP24A1 are enzymes that metabolize vitamin D and its analogs, with the structure of CYP3A4 being known but CYP24A1's structure remaining unknown.
  • Researchers used the known 3D structure of CYP3A4 to model how it interacts with different analogs of vitamin D to predict their metabolic conversion.
  • The findings suggest that the binding strength of vitamin D analogs to CYP3A4 can help explain their conversion by CYP24A1, despite CYP24A1's structure not being characterized.

Article Abstract

The microsomal cytochrome P450 3A4 (CYP3A4) and mitochondrial cytochrome P450 24A1 (CYP24A1) hydroxylating enzymes both metabolize vitamin D and its analogs. The three-dimensional (3D) structure of the full-length native human CYP3A4 has been solved, but the respective structure of the main vitamin D hydroxylating CYP24A1 enzyme is unknown. The structures of recombinant CYP24A1 enzymes have been solved; however, from studies of the vitamin D receptor, the use of a truncated protein for docking studies of ligands led to incorrect results. As the structure of the native CYP3A4 protein is known, we performed rigid docking supported by molecular dynamic simulation using CYP3A4 to predict the metabolic conversion of analogs of 1,25-dihydroxyvitamin D2 (1,25D2). This is highly important to the design of novel vitamin D-based drug candidates of reasonable metabolic stability as CYP3A4 metabolizes ca. 50% of the drug substances. The use of the 3D structure data of human CYP3A4 has allowed us to explain the substantial differences in the metabolic conversion of the side-chain geometric analogs of 1,25D2. The calculated free enthalpy of the binding of an analog of 1,25D2 to CYP3A4 agreed with the experimentally observed conversion of the analog by CYP24A1. The metabolic conversion of an analog of 1,25D2 to the main vitamin D hydroxylating enzyme CYP24A1, of unknown 3D structure, can be explained by the binding strength of the analog to the known 3D structure of the CYP3A4 enzyme.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9322940PMC
http://dx.doi.org/10.3390/ijms23147845DOI Listing

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