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Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules
Published on: July 25, 2013
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Protein structure based rational design of ecdysone agonists
Graham Holmwood1, Michael Schindler
1Bayer CropScience AG, Alfred-Nobel-Str. 50, 40789 Monheim, Germany.
Bioorganic & Medicinal Chemistry
|January 27, 2009
Summary
Protein X-ray crystallography guides the rational design of novel insecticides targeting the insect-specific Ecdysone receptor (EcR). This approach yields new chemical classes of safer insecticides by overcoming limitations of traditional structure-activity relation methods.
Area of Science:
- Structural Biology
- Insecticide Discovery
- Molecular Entomology
Background:
- The Ecdysone receptor (EcR) is a validated target for developing safe, insect-specific insecticides.
- Traditional structure-activity relation methods (QSARs, 2D-Hansch, 3D-CoMFA/CoMSIA) offer limited insight into EcR ligand interactions.
- The flexible nature of the EcR ligand-binding site necessitates advanced structural information for rational drug design.
Purpose of the Study:
- To review the impact of protein X-ray crystallography on the rational design of EcR agonists.
- To highlight the advantages of structural insights over ligand-based methods for insecticide discovery.
- To present new chemical classes of insecticides developed using protein structural data.
Main Methods:
- Protein X-ray crystallography for determining EcR ligand-binding domain structures.
- Structure-guided design of novel ecdysone agonist molecules.
- Evaluation of new insecticide candidates based on EcR agonism.
Main Results:
- Protein X-ray crystallography provides crucial insights into the EcR ligand-binding site, surpassing traditional QSAR approaches.
- The flexibility of the EcR binding site is better understood through structural studies, enabling more precise drug design.
- Several new non-steroidal chemical classes of ecdysone agonists have been successfully designed and identified.
Conclusions:
- Protein X-ray crystallography is a powerful tool for the rational design of insecticides targeting the EcR.
- Structure-guided design leads to the discovery of novel insecticide classes with potentially improved safety profiles.
- Understanding EcR structural dynamics is key to developing effective and selective insect control agents.
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01:22Protein Folding
Overview
02:26Conservation of Protein Domains Over Different Proteins
Protein domains are small structurally independent units that are part of a single amino acid chain. Although these domains are often structurally independent, they may rely on synergistic effects to perform their functions as part of a larger protein. Protein domains may be conserved within the same organism, as well as across different organisms.
A limited set of protein domains often duplicate and recombine during evolution. These domains can be organized in different combinations to form...
A limited set of protein domains often duplicate and recombine during evolution. These domains can be organized in different combinations to form...
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...
01:24Protein Organization
Proteins are polymers of amino acid residues. They are versatile and responsible for different cellular functions, including DNA replication, molecular transport, catalysis, and structural support. Proteins have a hierarchical structure comprising at least three levels of organization: primary, secondary, and tertiary structure. Some large proteins have a quaternary structure where individual protein subunits are linked together.
The primary structure of a protein is its amino acid sequence.
The primary structure of a protein is its amino acid sequence.
01:25Protein Folding
Proteins are chains of amino acids linked together by peptide bonds. Upon synthesis, a protein folds into a three-dimensional conformation, critical to its biological function. Interactions between its constituent amino acids guide protein folding, and hence the protein structure is primarily dependent on its amino acid sequence.
Protein Structure Is Critical to Its Biological Function
Proteins perform a wide range of biological functions such as catalyzing chemical reactions, providing...
Protein Structure Is Critical to Its Biological Function
Proteins perform a wide range of biological functions such as catalyzing chemical reactions, providing...
01:28Structure-Activity Relationships and Drug Design
Drug design is a dynamic field that involves discovering and developing new medications based on specific biological targets. This process heavily relies on structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) to guide the design and optimization of efficient drugs.
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence its...
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence its...