Structure-Based Design

Structure Based Design is a powerful method for rapidly identifying new lead compounds when a receptor structure is available. In the early stages of drug discovery, virtual high throughput screening (vHTS) can lead to increased efficiency by helping to prioritize compounds in a library and by reducing library size. During the lead optimization stage, accurate docking methods, efficient de novo design methods, and accurate physics-based scoring can yield high-confidence compounds that are more likely to be active in vivo. You can perform such tasks as:

• Using the structure of the receptor to identify and/or optimize small molecule lead compounds
• Make use of the receptor binding site shape to effectively run a High Throughput Screening (HTS) program.  
• Rapidly prioritize thousands or millions of ligand poses that result from vHTS using information from the structure of the receptor.
• Increase the accuracy of ligand pose predictions in the receptor site and the calculation of interaction energies using the state-of-the-art physics-based modeling and simulation engines.
• Perform flexible docking in which the docking of small molecules is influenced by existing low-energy conformations of side chains in the receptor binding site.

Related Application note:
Automated De Novo Design Workflow with Physics-Based Scoring Function for Fast Lead Identification and Optimization

Structure-Based Pharmacophores

New pharmacophore tools have been designed to seamlessly integrate structural data with ligand data to guide drug design. These tools allow you to generate pharmacophore models directly from protein active sites and use these models to rapidly screen large databases for new ligands. This information can also be integrated with ligand-based pharmacophore data to augment structural data with ligand-based data. Pharmacophore models from multiple protein active sites can also be used collectively to panel a ligand or set of ligands against multiple protein active sights. The pharmacophore, in the context of the ligand binding site, can also be used as a starting point for fragment-based design.

Related Products and Services

• Discovery Studio Structure-Based Design Software can be used to perform virtual high throughput screening, de novo evolution, and refined docking & scoring. Related software modules include:
  • DS LigandFit - Gain direct insight into the complementary features of ligands
  • DS LibDock - Perform efficient docking by using polar and apolar features (hotspots)
  • DS LigandScore - Evaluate ligand-protein interactions with well-validated and trained scoring functions
  • DS Ludi - Rapidly identify drug-like scaffolds from interaction sites in the receptor binding pocket
  • DS De Novo Evolution - Generate complete, drug-like molecules by linking and growing fragments onto a scaffold
  • DS Flexible Docking - Perform flexible docking in which the docking of small molecules is influenced by existing low-energy conformations of side chains in the binding site.
• Discovery Studio Simulation Software can also help in the study of protein-protein docking; particular modules of interest include:
  • Discovery Studio CHARMm - industry-standard molecular mechanics and dynamics software program
  • Discovery Studio CHARMm Lite - perform in situ ligand minimization using the well-validated CHARMm and CFF forcefields and several minimization algorithms
• Discovery Studio Pharmacophore Modeling and Analysis Software can be used to perform structure-based pharmacophore modeling, fragment-based design, and more . Related software modules:
  • DS Structure Based Pharmacophore - Generate pharmacophore models from protein structures
  • Ligand Profiler - Panel a ligand or set of ligands against multiple protein active sites
  • DS De Novo Ligand Builder - Use pharmacophores to guide the placement of fragments and generate novel lead compounds
• Contract Research & Scientific Consulting Services - through access to our full suite of software, the experienced computational scientists at Accelrys can collaborate with you with on your projects