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Related Concept Videos

Ligand Binding Sites02:40

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 Interfaces02:04

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...
Conserved Binding Sites01:49

Conserved Binding Sites

Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally analyses the...
The Equilibrium Binding Constant and Binding Strength02:18

The Equilibrium Binding Constant and Binding Strength

The equilibrium binding constant (Kb) quantifies the strength of a protein-ligand interaction. Kb can be calculated as follows when the reaction is at equilibrium:
Ligand Binding and Linkage00:49

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...
Ligand Binding Sites02:40

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...

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A general and fast scoring function for protein-ligand interactions: a simplified potential approach.

I Muegge1, Y C Martin

  • 1Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-6100, USA. ingo.muegge.b@bayer.com

Journal of Medicinal Chemistry
|March 12, 1999
PubMed
Summary

A new potential-based method estimates protein-ligand binding affinity using structural data. This knowledge-based approach, potentials of mean force (PMF), offers a general, parameter-free scoring function for drug discovery.

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Area of Science:

  • Computational chemistry
  • Structural biology
  • Drug discovery

Background:

  • Accurate estimation of protein-ligand binding affinity is crucial for drug discovery.
  • Existing methods often rely on empirical parameters or extensive training data.
  • A general, knowledge-based approach is needed for robust binding affinity prediction.

Purpose of the Study:

  • To present a fast, simplified potential-based method for estimating protein-ligand binding affinity.
  • To develop a general, knowledge-based scoring function utilizing structural information.
  • To validate the method's performance against experimental binding affinities.

Main Methods:

  • Exploited structural information from known protein-ligand complexes in the Protein Data Bank.
  • Converted structural data into distance-dependent Helmholtz free interaction energies (potentials of mean force, PMF).
  • Incorporated a reference state and a correction term for ligand volume to implicitly handle solvation and entropic contributions.

Main Results:

  • Significant correlation found between experimental binding affinities and the computed PMF score.
  • For 77 protein-ligand complexes, the score showed a standard deviation of 1.8 log Ki units (R2=0.61).
  • Superior performance observed for serine protease (1.0 log Ki, R2=0.86) and HIV-1 protease complexes (0.8 log Ki, R2=0.74).
  • The PMF score outperformed other scoring functions (Böhm's, SMOG) on most test sets.

Conclusions:

  • The developed potential-based method provides a general and accurate approach for predicting protein-ligand binding affinity.
  • The method does not require prior knowledge of measured binding affinities, making it broadly applicable.
  • The potentials of mean force (PMF) scoring function shows promise for integration into molecular docking studies.