Exploring Product Release from Yeast Cytosine Deaminase with Metadynamics

Overview

Journal J Phys Chem B

Publisher American Chemical Society

Specialty Chemistry

Date 2024 Mar 22

PMID 38516924

Authors

Kayla A Croney

James McCarty

Affiliations

Soon will be listed here.

Abstract

The yeast cytosine deaminase (yCD) enzyme/5-fluorocytosine prodrug system is a promising candidate for targeted chemotherapeutics. After conversion of the prodrug into the toxic chemotherapeutic drug, 5-fluorouracil (5-FU), the slow product release from the enzyme limits the overall catalytic efficiency of the enzyme/prodrug system. Here, we present a computational study of the product release of the anticancer drug, 5-FU, from yCD using metadynamics. We present a comparison of the 5-FU drug to the natural enzyme product, uracil. We use volume-based metadynamics to compute the free energy landscape for product release and show a modest binding affinity for the product to the enzyme, consistent with experiments. Next, we use infrequent metadynamics to estimate the unbiased release rate from Kramers time-dependent rate theory and find a favorable comparison to experiment with a slower rate of product release for the 5-FU system. Our work demonstrates how adaptive sampling methods can be used to study the protein-ligand unbinding process for engineering enzyme/prodrug systems and gives insights into the molecular mechanism of product release for the yCD/5-FU system.

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PMID: 39143923 PMC: 11351021. DOI: 10.1021/acs.jcim.4c00966.

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