Structure-based Design
Comprehensive, Scalable Portfolio of Scientific Tools to Support Structure-based and Fragment-based Design
Facilitate Drug Discovery From Hit Discovery to Late-stage Optimization
Structure-Based Design (SBD) and the related Fragment-Based Design (FBD) are well established strategies in the rational development of small molecule drugs. Knowledge of how a small molecule binds into a protein affords considerable advantages, both in terms of prioritizing compounds for early stage screening, through to optimizing potency and selectivity.
BIOVIA Discovery Studio delivers a comprehensive, scalable portfolio of scientific tools, including GOLD from the Cambridge Crystallographic Data Centre (CCDC), to support and assist SBD and FBD strategies from hit discovery to late-stage lead optimization.
- Prepare
- Screen
- Score
- Extend
Prepare
- Analyze and prepare 3D structures (e.g., PDB, X-ray structure, homology model) for SBD
- Automatically build neighboring molecules based on crystal packing and analyze their interactions
- Predict residue ionization states at chosen pH
- Identify and study putative ligand binding sites
- Prepare ligands with extensive set of characteristics and calculate 3D coordinates
- Generate ligand conformations
- Filter ligands based on drug-likeness, molecular properties, or to remove undesirable groups or features
Screen
- Hit Identification and optimization
- Perform virtual screening on ligands and fragments using either the CATALYST pharmacophore engine, or the LibDock or CDOCKER docking approaches
- Perform docking with GOLD §
- Perform in situ lead optimization using classical medicinal chemistry reaction transformations and commercially-available reagents
- Scaffold-hop or perform R-group substitutions in situ using molecular fragments derived from commercially-available compounds
§ Requires license from Cambridge Crystallographic Data Centre
Score
- Calculate binding energies with MM-PBSA or MM-GBSA CHARMm-based methods
- Accurately predict relative ligand binding energy for a congeneric ligand series using the free energy perturbation (FEP) method
- Calculate the relative free energy of binding for a combinatorial library of ligands modeled by Multi-Site Lambda Dynamics (MSLD)
- Identify critical interacting residues using a comprehensive set of favorable, unfavorable and unsatisfied non-bond monitors
- Profile and prioritize screening hits, optimizing potency and target specificity
Extend
- Design and optimize combinatorial libraries as new starting points for further screening.
- Combine your scores with classical QSAR, fingerprints, and Quantum Mechanics based descriptors and create advanced predictive models
- Minimize toxicity using TOPKAT and optimize the pharmacokinetic profile.
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