Volume 252, 2024

Exploring the selectivity of cytochrome P450 for enhanced novel anticancer agent synthesis

Abstract

Cytochrome P450 monooxygenases are an extensive and unique class of enzymes, which can regio- and stereo-selectively functionalise hydrocarbons by way of oxidation reactions. These enzymes are naturally occurring but have also been extensively applied in a synthesis context, where they are used as efficient biocatalysts. Recently, a biosynthetic pathway where a cytochrome P450 monooxygenase catalyses a critical step of the pathway was uncovered, leading to the production of a number of products that display high antitumour potency. In this work, we use computational techniques to gain insight into the factors that determine the relative yields of the different products. We use conformational search algorithms to understand the substrate stereochemistry. On a machine-learned 3D protein structure, we use molecular docking to obtain a library of favourable poses for substrate–protein interaction. With molecular dynamics, we investigate the most favourable poses for reactivity on a molecular level, allowing us to investigate which protein–substrate interactions favour a given product and thus gain insight into the product selectivity.

Graphical abstract: Exploring the selectivity of cytochrome P450 for enhanced novel anticancer agent synthesis

  • This article is part of the themed collection: Biocatalysis

Associated articles

Supplementary files

Article information

Article type
Paper
Submitted
08 jan 2024
Accepted
28 feb 2024
First published
28 feb 2024
This article is Open Access
Creative Commons BY license

Faraday Discuss., 2024,252, 69-88

Exploring the selectivity of cytochrome P450 for enhanced novel anticancer agent synthesis

J. Čivić, N. R. McFarlane, J. Masschelein and J. N. Harvey, Faraday Discuss., 2024, 252, 69 DOI: 10.1039/D4FD00004H

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