Computational Simulations to Guide Enzyme-Mediated Prodrug Activation.

Milica Markovic,Shimon Ben-Shabat,Arik Dahan

doi:10.3390/ijms21103621

Milica Markovic, Shimon Ben-Shabat + Show 1 more

Open Access

https://doi.org/10.3390/ijms21103621

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Abstract

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.

Highlights

Prodrug is a drug derivative intended to undergo chemical/enzymatic activation and thereby release an active parent drug, which is free to achieve its pharmacological effect in the body [1]
We developed an molecular dynamics (MD) simulation in order to determine energetic changes of the PL-drug conjugates in the active site of phospholipase A2 (PLA2) [39,40,41,42]
A potent way of overcoming these limitations is the use of quantum mechanics (QM)/molecular mechanics (MM) calculations, in which the system is divided into QM and MM regions, where QM regions deal with the electrons in a small area, and a larger part of the protein, the solvent and any other groups connected to the protein are modeled by MM

Summary

Introduction

Prodrug is a drug derivative intended to undergo chemical/enzymatic activation and thereby release an active parent drug, which is free to achieve its pharmacological effect in the body [1]. Prodrugs constitute a useful approach for altering physicochemical drug properties (e.g., solubility) and for optimizing drug-like features of active compounds (i.e., absorption, distribution, metabolism and excretion (ADME)) [5,6]. The crucial step in the successful prodrug design is the inclusion of the activation mechanism that releases an active parent drug from a prodrug molecule in an efficient/controlled way, in order to achieve a successful therapeutic effect. Prodrug activation can be achieved through enzyme-mediated hydrolysis or oxidation/reduction processes or through chemical degradation within the body, triggered via a particular stimulus. Numerous enzymes can be involved in the activation of prodrugs; some examples include oxidoreductases like CYP450, and hydrolytic enzymes such as carboxylesterase, butyrylcholinesterase, acetylcholinesterase, paraoxonase, β-glucuronidase, matrix metalloproteinase, alkaline phosphatase (ALP), phospholipase A2 (PLA2), human valacyclovirase and others [8,9]

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