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Enzyme Inhibition

Enzyme Inhibition

Inhibitors are molecules that reduce enzyme activity by binding to the enzyme. In a normally functioning cell, enzymes are regulated by a variety of inhibitors. Drugs and other toxins can also inhibit enzymes. Some inhibitors bind to the enzyme’s active site, while others inhibit enzymatic activity by binding to other sites on the protein structure.

Enzymes

Enzymes

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...

Ligand Binding Sites

Ligand Binding Sites

Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...

Protein-protein Interfaces

Protein-protein Interfaces

Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a polypeptide...

Ligand Binding and Linkage

Ligand Binding and Linkage

Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence the...

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Related Experiment Video

Updated: May 22, 2026

Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules

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Published on: July 25, 2013

Template-Based Docking Using Automated Maximum Common Substructure Identification with EnzyDock: Mechanistic and

Renana Schwartz¹, Amit Hadar-Volk¹, Kwangho Nam²

¹Department of Chemistry, Israel National Institute of Energy Storage (INIES) and Institute for Nanotechnology & Advanced Materials, Bar-Ilan University, Ramat-Gan 5290002, Israel.

Journal of Chemical Information and Modeling

|May 19, 2025

Summary

EnzyDock now uses Maximum Common Substructure (MCS) for enhanced mechanistic docking, modeling enzyme reactions from substrates to products. This strategy improves docking accuracy for diverse ligands and reaction intermediates.

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Published on: November 22, 2024

Area of Science:

Computational Chemistry
Structural Biology
Enzymology

Background:

Mechanistic docking requires modeling multiple ligand states (substrates, intermediates, products) within an enzyme's active site.
Existing docking programs often struggle with accurately representing the full reaction coordinate.
EnzyDock previously enabled multistate, multiscale CHARMM-based docking, including consensus docking.

Purpose of the Study:

To implement and evaluate a Maximum Common Substructure (MCS)-guided docking strategy within EnzyDock.
To enable automatic detection of ligand similarity for efficient docking along enzyme reaction coordinates.
To demonstrate the utility of MCS-guided docking for both mechanistic enzyme studies and inhibitor design.

Main Methods:

Implementation of an MCS multistate approach integrated into the EnzyDock program.
Application to complex enzyme reaction cascades (CotB2, LepI) for mechanistic docking.
Docking of enzyme inhibitors to dihydrofolate reductase and SARS-CoV-2 Mpro, utilizing covalent docking and QM/MM scoring.

Main Results:

The MCS strategy enables efficient and robust docking of ligands along enzyme reaction coordinates.
Different MCS protocols were identified as necessary for achieving mechanistic consistency versus docking diverse inhibitors.
Successful application to complex enzyme systems and inhibitor docking, including covalent interactions.

Conclusions:

MCS-guided docking is an effective strategy for robust mechanistic enzyme docking and inhibitor design.
The developed approach enhances EnzyDock's capabilities for modeling enzyme reactions and diverse ligands.
The findings are expected to be transferable to other molecular docking programs.