Structure Based Design

SYBYL’s Structure Based Design Capabilities

Structure-based design capabilities in SYBYL-X allow researchers to understand and rationalize drug interactions with its receptor, to identify potential new binding interactions that will provide ‘step jumps’ in potency, or to identify options for improving ADME or physical properties without disrupting key receptor interactions. SYBYL-X users can:

  • Build a 3D structural model or homology model for the receptor of interest
  • Identify and visualize the cavities present on your target protein and visualize the properties of the protein/ligand interaction surface
  • Predict and rationalize potential drug interactions with its receptor using Surflex-Dock, a world class docker that has been extensively validated and favorably compared to all leading competing methods by independent researchers
  • Design fragment collections used for screening to perform virtual screening of fragment libraries, and once interesting fragments are identified, to elaborate the fragment into structures or design a library of structures that will fit to a receptor cavity
  • Identify promising lead candidates using Surflex Dock for virtual screening of databases of in-house or commercially available compounds

The SYBYL-X Suite includes:

  • Surflex-Dock™ offers unparalleled enrichments in virtual high-throughput screening and accurate prediction for ligand binding mode and conformation. Its users can customize scoring functions, consider protein flexibility, multiple binding site detection and docking, and key fragment constraints. Surflex-Dock is the top choice for lead discovery, scaffold replacement, lead optimization and fragment based discovery.
  • Advanced Protein Modeling (APM) for protein homology modeling enables users to perform both homolog finding and comparative modeling through a streamlined interface. APM finds more relevant homologs to start the modeling process because it takes advantage of environment-specific substitution tables, structure-dependent gap penalties, automated alignment method selection, and the highly annotated HOMSTRAD database. Homologs are structurally aligned based using homology and local structural environment, and then structurally conserved regions are identified using backbone curvature and torsion in addition to C-alpha rmsd and homology. Loops (structurally variable regions) are then modeled by knowledge-based or ab initio approaches, and sidechains are added by enumerating rotamer combinations constrained by borrowing as much information from the parent homologs as possible. A range of analysis tools are available to highlight potential problems with the structure and allow the user to iterate through the process and refine initial models.
  • MOLCAD creates graphical images that reveal molecules’ essential properties for recognition. MOLCAD calculates and displays the surfaces of both small molecule drugs and macromolecular targets and can identify channels and cavities that may be potential binding sites. A broad range of properties can be mapped onto these surfaces to rationalize the properties of the binding site and ligand/receptor complementarity.

Learn more about the SYBYL-X Suite:

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