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MotifLeadDB: A Hierarchical Structural Data Set for Congeneric Ligand Binding Activity Change
Nawoon Kim1,2, Byunghyun Bae1,3, Nuri Jung3
1Biomedical Research Division, Korea Institute of Science and Technology, Seongbuk-gu 02792, Republic of Korea.
Journal of Chemical Information and Modeling
|May 20, 2026
Summary
We created MotifLeadDB, a novel structural database for drug discovery. This dataset aids in understanding structure-activity relationships and improving computational models for predicting ligand binding affinity changes.
Area of Science:
- Computational chemistry
- Structural biology
- Drug discovery
Background:
- Predicting ligand binding free energy changes from chemical substitutions is crucial for drug optimization.
- Current computational methods lack accuracy due to insufficient training data.
Purpose of the Study:
- To construct MotifLeadDB, a structural model dataset for hit-to-lead optimization.
- To provide a resource for understanding structure-activity relationships and training predictive models.
Main Methods:
- Grouped congeneric ligands by scaffolds for each receptor.
- Built protein-ligand complex structural models with ligand and side-chain optimization.
- Guided ligand docking using experimental structures with chemical similarity.
Main Results:
- Developed MotifLeadDB with 342,489 protein-ligand complex structural models.
- Organized models into 27,077 ligand scaffolds across 357 nonredundant receptors.
- Included confidence levels for all generated structural models.
Conclusions:
- MotifLeadDB facilitates direct inference of structural basis for energy changes upon substitution.
- The dataset can be used for case studies and training computational models for binding activity prediction.
Related Concept Videos
02:40Ligand 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-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...
02:40Ligand 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-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...
00:49Ligand 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...
00:49Ligand 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...
01:49Conserved 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...
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...
02:18The 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: