Issue 44, 2021

The molecular mechanism of P450-catalyzed amination of the pyrrolidine derivative of lidocaine: insights from multiscale simulations

Abstract

Nitrogen heterocycles are key and prevalent motifs in drugs. Evolved variants of cytochrome P450BM3 (CYP102A1) from Bacillus megaterium employ high-valent oxo-iron(IV) species to catalyze the synthesis of imidazolidine-4-ones via an intramolecular C–H amination. Herein, we use multi-scale simulations, including classical molecular dynamics (MD) simulations, quantum mechanical/molecular mechanical (QM/MM) calculations and QM calculations, to reveal the molecular mechanism of the intramolecular C–H amination of the pyrrolidine derivative of lidocaine bearing cyclic amino moieties catalyzed by the variant RP/FV/EV of P450BM3, which bears five mutations compared to wild type. Our calculations show that overall catalysis includes both the enzymatic transformation in P450 and non-enzymatic transformation in water solution. The enzymatic transformation involves the exclusive hydroxylation of the C–H bond of the pyrrolidine derivative of lidocaine, leading to the hydroxylated intermediate, during which the substrate radical would be bypassed. The following dehydration and C–N coupling reactions are found to be much favored in aqueous situation compared to that in the non-polar protein environment. The present findings expand our understanding of the P450-catalyzed C(sp3)–H amination reaction.

Graphical abstract: The molecular mechanism of P450-catalyzed amination of the pyrrolidine derivative of lidocaine: insights from multiscale simulations

Supplementary files

Article information

Article type
Paper
Submitted
12 Jūn. 2021
Accepted
09 Aug. 2021
First published
16 Aug. 2021
This article is Open Access
Creative Commons BY-NC license

RSC Adv., 2021,11, 27674-27680

The molecular mechanism of P450-catalyzed amination of the pyrrolidine derivative of lidocaine: insights from multiscale simulations

C. Wang, P. Wu, Z. Wang and B. Wang, RSC Adv., 2021, 11, 27674 DOI: 10.1039/D1RA04564D

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