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Related Concept Videos

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 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...
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...
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...
Protein-Drug Binding: Determination Methods01:22

Protein-Drug Binding: Determination Methods

Determining protein-drug binding can be achieved through indirect and direct methods, each providing valuable insights into the interaction between proteins and drugs.
Indirect methods involve isolating the bound drug from its free form in biological samples such as blood, serum, or plasma. These techniques aim to measure the percentage of drugs bound to proteins. Equilibrium dialysis is a commonly used method where the free drug concentration at equilibrium is measured by separating the bound...
Quantitative Aspects of Drug-Receptor Interaction01:30

Quantitative Aspects of Drug-Receptor Interaction

The receptor occupancy theory connects a drug's response to the number of occupied receptors. With higher drug concentrations, more receptors are occupied, leading to increased responses. The formation of drug-receptor complexes involves association and dissociation rates, which reach equilibrium when the forward and backward reactions are equal. The equilibrium association constant (Ka) and its inverse, the equilibrium dissociation constant (Kd), indicate drug affinity. Higher Ka and lower Kd...

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Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules
10:58

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

Published on: July 25, 2013

An efficient computational method for calculating ligand binding affinities.

Atsushi Suenaga1, Noriaki Okimoto, Yoshinori Hirano

  • 1Computational Biology Research Center, National Institute of Advanced Industrial Science and Technology, Koto-ku, Tokyo, Japan. atsushi.suenaga@aist.go.jp

Plos One
|August 24, 2012
PubMed
Summary
This summary is machine-generated.

We developed a new computational method, multiple random conformation/molecular mechanics generalized Born/surface area (MRC-MM-GBSA), to accurately predict protein-ligand binding affinity for drug discovery. This method improves upon traditional docking scores for lead compound identification.

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Area of Science:

  • Computational chemistry
  • Drug discovery
  • Biophysics

Background:

  • Molecular docking is crucial for identifying drug lead compounds, but its scoring functions lack precision in predicting protein-ligand binding affinity.
  • Accurate binding affinity prediction is essential for efficient drug design and development.

Purpose of the Study:

  • To develop an efficient and accurate computational method for calculating protein-ligand binding affinity.
  • To improve the precision of binding affinity predictions beyond traditional molecular docking scores.

Main Methods:

  • Developed the multiple random conformation/molecular mechanics generalized Born/surface area (MRC-MM-GBSA) method.
  • Utilized Jarzynski identity and MM-GBSA calculations.
  • Generated multiple protein-ligand conformations to estimate work distribution, avoiding explicit pulling simulations.

Main Results:

  • MRC-MM-GBSA scores showed good qualitative agreement with experimental binding affinities for four target proteins.
  • The method accurately calculated the free energy difference of ligand binding (ΔΔG) with an error of approximately ± 1.5 kcal/mol.
  • MRC-MM-GBSA demonstrated superior ligand ranking effectiveness, especially for flexible target proteins, compared to single-conformation MM-GBSA.

Conclusions:

  • MRC-MM-GBSA offers a computationally efficient and accurate approach for ranking ligands by binding affinity in post-docking analysis.
  • The method provides a reliable means to compare calculated binding affinities with experimental values.
  • This advancement facilitates more precise lead compound identification in drug discovery pipelines.