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Computational Simulations to Guide Enzyme-Mediated Prodrug Activation

Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, 8410501 Beer-Sheva, Israel
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(10), 3621;
Received: 28 April 2020 / Revised: 18 May 2020 / Accepted: 19 May 2020 / Published: 20 May 2020
(This article belongs to the Special Issue New Avenues in Molecular Docking for Drug Design 2020)
Prodrugs are designed to improve pharmaceutical/biopharmaceutical characteristics, pharmacokinetic/pharmacodynamic properties, site-specificity, and more. A crucial step in successful prodrug is its activation, which releases the active parent drug, exerting a therapeutic effect. Prodrug activation can be based on oxidation/reduction processes, or through enzyme-mediated hydrolysis, from oxidoreductases (i.e., Cytochrome P450) to hydrolytic enzymes (i.e., carboxylesterase). This study provides an overview of the novel in silico methods for the optimization of enzyme-mediated prodrug activation. Computational methods simulating enzyme-substrate binding can be simpler like molecular docking, or more complex, such as quantum mechanics (QM), molecular mechanics (MM), and free energy perturbation (FEP) methods such as molecular dynamics (MD). Examples for MD simulations used for elucidating the mechanism of prodrug (losartan, paclitaxel derivatives) metabolism via CYP450 enzyme are presented, as well as an MD simulation for optimizing linker length in phospholipid-based prodrugs. Molecular docking investigating quinazolinone prodrugs as substrates for alkaline phosphatase is also presented, as well as QM and MD simulations used for optimal fit of different prodrugs within the human carboxylesterase 1 catalytical site. Overall, high quality computational simulations may show good agreement with experimental results, and should be used early in the prodrug development process. View Full-Text
Keywords: prodrug; enzymatic activation; in silico modeling; DFT; quantum mechanics; molecular mechanics; molecular dynamics; molecular docking prodrug; enzymatic activation; in silico modeling; DFT; quantum mechanics; molecular mechanics; molecular dynamics; molecular docking
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MDPI and ACS Style

Markovic, M.; Ben-Shabat, S.; Dahan, A. Computational Simulations to Guide Enzyme-Mediated Prodrug Activation. Int. J. Mol. Sci. 2020, 21, 3621.

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