Metabolism of 4-Aminopiperidine Drugs by Cytochrome P450s: Molecular and Quantum Mechanical Insights into Drug Design

4-Aminopiperidines are a variety of therapeutic agents that are extensively metabolized by cytochrome P450s with CYP3A4 as a major isoform catalyzing their N-dealkylation reaction. However, its catalytic mechanism has not been fully elucidated in a molecular interaction level. Here, we applied theoretical approaches including the molecular mechanics-based docking to study the binding patterns and quantum mechanics-based reactivity calculations. They were supported by the experimental human liver microsomal clearance and P450 isoform phenotyping data. Our results herein suggested that the molecular interactions between substrates and CYP3A4 active site residues are essential for the N-dealkylation of 4-aminopiperidines. We also found that the serine 119 residue of CYP3A4 may serve as a key hydrogen-bonding partner to interact with the 4-amino groups of the studied drugs. The reactivity of the side chain α-carbon hydrogens drives the direction of catalysis as well. As a result, structure-based drug design approaches look promising to guide drug discovery programs into the optimized drug metabolism space

Model calibration against CB1Ra data.

<p>The calibrated model shows good agreement between model simulations (black) and experimental BW (A). The fitted model trajectories show poor agreement with FFM (B) and FM (C) measurements at the three drug dose levels. Gray region indicates the intervention phase in each study. Error bars represent SEM (9-10 rats).</p

Body composition data for CR and CB1Ra treatment studies.

<p>Different color curves show changes in body composition in response to different levels of CR (A) and CB1Ra (B). Changes in FFM and FM in (A) and (B) do not appear along a single pre-defined FFM-FM curve (dashed line) defined by the energy partition function [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0155674#pone.0155674.ref007" target="_blank">7</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0155674#pone.0155674.ref008" target="_blank">8</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0155674#pone.0155674.ref021" target="_blank">21</a>]. The different shapes correspond to three time points when BC measurements were taken. The colored line segments connecting data points are meant to guide the reader’s eye. Error bars represent SEM (9-10 rats).</p

The α-free model fits BC in CR and CB1Ra BC studies.

<p>Simulations (black) of the <i>α</i>-free model show agreement with FFM (red) and FM (yellow) measurements in CR (A) and CB1Ra (B) intervention studies. Gray region indicates treatment phases in the two studies. Error bars represent SEM (9-10 rats).</p

The α-free model allows for estimation of body composition changes compared to the two-dimensional model.

<p>Body composition simulations of the <i>α</i>-free model (blue) can be used to estimate FM and FFM outside of measured time points, black. The two-dimensional model simulation based on the <i>α</i> function (red) is unable to accurately capture changes in FM and FFM (purple). Only data for the 30 mg/kg dose is shown, with the purple line segments meant to guide the reader’s eye. Error bars represent SEM (9-10 rats).</p

Model calibration against CR data.

<p>The calibrated model shows good agreement between model simulations (black) and experimental BW (A), FFM (B), and FM (C) measurements at all caloric restriction levels. Gray region indicates the intervention phase in each study. Error bars represent SEM (9-10 rats).</p