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

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.

Nonaqueous Capillary Electrophoretic Separation of Analogs of (24R)-1,24-Dihydroxyvitamin D3 Derivative as Predicted by Quantum Chemical Calculations

“…However, experimental methods are labor-intensive and expensive. For this reason, analog synthesis is being optimized using new methods, such as quantum mechanical calculations [ 38 , 39 ]. In recent years, quantum chemical (QC) methods have emerged as an efficient tool for the accurate prediction of stability and chemical reactivity of molecules [ 40 , 41 , 42 ].…”

Novel Strategies in the Development of New Therapies, Drug Substances, and Drug Carriers Volume II

“…Metabolic resistance determines the lifetime and, therefore, the applicability of a compound as a drug substance candidate. For this reason, Żołek et al [ 12 ] performed rigid docking supported by molecular dynamics simulation using the known structure of the native CYP3A4 enzyme to predict the metabolic resistance of analogs of 1,25-dihydroxyvitamin D 2 (1,25D2) in vivo. The microsomal cytochrome P450 3A4 (CYP3A4) and mitochondrial cytochrome P450 24A1 (CYP24A1) hydroxylating enzymes both metabolize vitamin D and its analogs.…”