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Related Concept Videos

Induced-fit Model01:13

Induced-fit Model

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Most chemical reactions in cells require enzymes—biological catalysts that speed up the reaction without being consumed or permanently changed. They reduce the activation energy needed to convert the reactants into products. Enzymes are proteins, that usually work by binding to a substrate—a reactant molecule that they act upon.
Enzymes exhibit substrate specificity, meaning that they can only bind to certain substrates. This is mainly determined by the shape and chemical...
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Enzymes02:34

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Inside living organisms, enzymes act as catalysts for many biochemical reactions involved in cellular metabolism. The role of enzymes is to reduce the activation energies of biochemical reactions by forming complexes with its substrates. The lowering of activation energies favor an increase in the rates of biochemical reactions.
Enzyme deficiencies can often translate into life-threatening diseases. For example, a genetic abnormality resulting in the deficiency of the enzyme G6PD...
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Introduction to Mechanisms of Enzyme Catalysis01:13

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For many years, scientists thought that enzyme-substrate binding took place in a simple "lock-and-key" fashion. This model stated that the enzyme and substrate fit together perfectly in one instantaneous step. However, current research supports a more refined view scientists call induced fit. The induced-fit model expands upon the lock-and-key model by describing a more dynamic interaction between enzyme and substrate. As the enzyme and substrate come together, their interaction causes...
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Enzymes and Activation Energy01:13

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The activation energy (or free energy of activation), abbreviated as Ea, is the small amount of energy input necessary for all chemical reactions to occur. During chemical reactions, certain chemical bonds break, and new ones form. For example, when a glucose molecule breaks down, bonds between the molecule's carbon atoms break. Since these are energy-storing bonds, they release energy when broken. However, the molecule must be somewhat contorted to get into a state that allows the bonds to...
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Prodrugs01:30

Prodrugs

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Prodrugs are a class of pharmaceutical compounds that undergo a biotransformation process within the body to be converted into a pharmacologically active drug. Prodrugs are designed to improve the therapeutic properties of the parent drug, such as enhancing bioavailability, increasing stability, or reducing toxicity. The concept of prodrugs revolves around modifying the chemical structure of the original drug to make it more effective or convenient for administration.
Prodrugs help overcome...
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Drug Discovery: Overview01:26

Drug Discovery: Overview

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Drug discovery is a multifaceted process involving extensive screening, testing, and optimization of lead compounds to identify potential new drugs for therapeutic use. It combines several approaches, including screening large numbers of natural products, chemical modification of known active molecules, identification of new drug targets, and rational design based on biological mechanisms and drug-receptor structure. These approaches are carried out in both academic research laboratories and...
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Updated: Dec 20, 2025

Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
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Computational Simulations to Guide Enzyme-Mediated Prodrug Activation.

Milica Markovic1, Shimon Ben-Shabat1, Arik Dahan1

  • 1Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel.

International Journal of Molecular Sciences
|May 24, 2020
PubMed
Summary

Computational methods accelerate prodrug development by optimizing enzyme-mediated activation. In silico simulations, including molecular docking and molecular dynamics, accurately predict drug metabolism and improve prodrug design.

Keywords:
DFTenzymatic activationin silico modelingmolecular dockingmolecular dynamicsmolecular mechanicsprodrugquantum mechanics

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Area of Science:

  • Medicinal Chemistry
  • Computational Chemistry
  • Pharmacology

Background:

  • Prodrugs enhance drug delivery and therapeutic efficacy.
  • Prodrug activation is essential for releasing the active parent drug.
  • Enzyme-mediated hydrolysis and oxidation/reduction are key activation pathways.

Purpose of the Study:

  • To review novel in silico methods for optimizing enzyme-mediated prodrug activation.
  • To highlight the application of computational simulations in prodrug design.
  • To demonstrate the predictive power of computational approaches in drug development.

Main Methods:

  • Molecular docking for enzyme-substrate binding analysis.
  • Molecular dynamics (MD) simulations for mechanism elucidation and optimization.
  • Quantum mechanics (QM) and free energy perturbation (FEP) for detailed binding studies.

Main Results:

  • MD simulations elucidated prodrug metabolism by CYP450 enzymes (e.g., losartan, paclitaxel derivatives).
  • MD simulations optimized linker length in phospholipid-based prodrugs.
  • Molecular docking and QM/MD simulations identified optimal fits for prodrugs in human carboxylesterase 1.

Conclusions:

  • High-quality computational simulations align well with experimental findings.
  • In silico methods should be integrated early in the prodrug development pipeline.
  • Computational approaches offer significant potential for rational prodrug design and optimization.