Related Experiment Video
Updated: Jul 19, 2025
08:49
Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
Published on: June 20, 2025
337
Worth the Weight: Sub-Pocket EXplorer (SubPEx), a Weighted Ensemble Method to Enhance Binding-Pocket Conformational
Erich Hellemann1, Jacob D Durrant1
1Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.
Journal of Chemical Theory and Computation
|August 16, 2023
Summary
This study introduces Sub-Pocket EXplorer (SubPEx), a new method using weighted ensemble path sampling to improve virtual screening by exploring multiple protein binding-pocket conformations. This enhances the discovery of drug candidates that bind to flexible protein targets.
Area of Science:
- Computational chemistry
- Drug discovery
- Structural biology
Background:
- Traditional structure-based virtual screening (VS) often fails to identify ligands binding to alternate protein conformations.
- Exploring protein binding-pocket flexibility is crucial for effective VS but challenging with existing methods.
- Ensemble docking requires robust pocket sampling techniques to incorporate multiple conformations.
Purpose of the Study:
- To introduce Sub-Pocket EXplorer (SubPEx), a novel approach for accelerated binding-pocket sampling.
- To enhance virtual screening by enabling the identification of ligands targeting diverse protein conformations.
- To demonstrate the utility of SubPEx in drug discovery contexts.
Main Methods:
- Sub-Pocket EXplorer (SubPEx) utilizes weighted ensemble (WE) path sampling to efficiently explore binding-pocket conformational space.
- The approach accelerates the sampling of protein flexibility relevant for ligand binding.
- SubPEx was applied to heat shock protein 90, influenza neuraminidase, and yeast hexokinase 2.
Main Results:
- SubPEx effectively accelerates binding-pocket sampling, addressing a key limitation in ensemble docking.
- The method was successfully applied to three diverse proteins critical in drug discovery.
- Proof-of-principle demonstrates SubPEx's potential for identifying ligands across different conformational states.
Conclusions:
- Sub-Pocket EXplorer (SubPEx) offers an advanced computational method for structure-based virtual screening.
- By improving pocket sampling, SubPEx can lead to the discovery of novel drug candidates targeting flexible proteins.
- The open-source availability of SubPEx facilitates its adoption in the broader drug discovery community.
Related Concept Videos
01:49Conserved Binding Sites
4.2K
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...
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...
4.2K
02:18The Equilibrium Binding Constant and Binding Strength
13.0K
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:
13.0K
02:40Ligand Binding Sites
12.9K
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-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...
12.9K
01:22Protein-Drug Binding: Determination Methods
238
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...
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...
238