CSD-Discovery - Discover new molecules
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CSD-Discovery is a software that allows discovery chemists to interrogate protein ligand complexes, dock small molecules, search for similar active ligands, propose replacements or modifications to scaffolds, and integrate these tools into internal systems. It brings together data from the Protein Data Bank and Cambridge Structural Database. The software includes components for protein-ligand docking, generating molecular conformations, aligning ligands flexibly, searching for scaffold replacements or patterns, and script-based interfaces. Case studies demonstrate using it to identify active enantiomers and understand conformational preferences to inform drug design.
CSD-Discovery - Discover new molecules
- 1. CSD-Discovery Discover new molecules Overview For discovery chemists, the components in CSD-Discovery provide the means to: • Interrogate protein ligand complexes • Dock small molecules, generate probable molecular conformations • Search for likely overlays of active ligands • Propose scaffold hops or isosteric replacements • Produce easy integrations into internal systems Bringing together the Protein Data Bank (PDB) and Cambridge Structural Database (CSD) and much more. CSD-Discovery components Protein-Ligand Docking Dock small molecules into proteins flexibly; optionally sampling protein flexibility and solvent location during docking using the world-renowned docking package, GOLD to provide fast and accurate binding mode prediction in lead discovery and lead optimisation. Generation of Molecular Conformations Generate plausible molecular conformations by using the wealth of information available in the Cambridge Structural Database rapidly and effectively to benefit ligand-based molecular screening and pharmacophore prediction. Flexible Alignment of Ligands Align ligands using generated conformations to build realistic pharmacophore hypotheses for use in field-based virtual ligand screening or scaffold hopping. Searching for Scaffold Hops and Pharmacophoric Patterns Mine both the CSD and the PDB using pharmacophores or substructure searching interactively to find repeated patterns of interactions or possible suggestions for potential scaffold hops using CSD-CrossMiner. Such information can lead to credible and non-obvious ideas and directions for lead development. Script-based Interfaces Create tailored Python scripts using the whole spectrum of CSD functionality to answer your targeted research questions. Integrate access to CSD-Discovery workflows seamlessly with 3rd party software.
- 2. info@ccdc.cam.ac.uk www.ccdc.cam.ac.uk UK: +44 1223 336408 Doc no. 107CSDD18 The Cambridge Crystallographic Data Centre Case studies (a) Probing enantiomeric specificity using side-chain and water flexibility in docking Understanding the selective inhibition of Adenosine Receptors (ARs) is of interest in drug discovery, as ARs mediate many physiological processes and so are potential therapeutic targets. Carbajales and co- workers1 explored the binding behaviour of new antagonists to the AR hA2BAR to determine which enantiomer was active in the binding site. Each docking needed to consider both side chain flexibility of certain binding residues and the role of water mediation in docking. Using GOLD, the team was able to identify that the S-form of their compound was binding to the target, and rationalise the role that side-chain motion and water plays in influencing binding. 1 C. Carbajales, J. Azuaje, A. Oliveira, H. Gutiérrez-de-Terán, E. Sotelo, et al., J. Med. Chem. (2017) 60, 3372-3382. (b) Using structural data to understand conformational preferences Conformational analysis is key to Drug Discovery, and the data in the Cambridge Structural Database can help. Kung and co-workers2 analysed the conformational preferences of substituted benzamides in the CSD to understand how substitution at the ortho position influenced the conformational preferences when targeting EZH2. By correlating the relative activities of compounds with the CCC=O torsion angle, they were able to understand and interpret the conformational needs of their lead molecules to have high potency. A cyclisation strategy then led to a new class of active compounds. 2 P.-P. Kung, E. Rui, S. Bergqvist, P. Bingham, W.-G. Zhang, R. A. Rollins, M. Edwards, et al., J. Med. Chem. (2016) 59, 8306–8325. How to find out more? Visit the CSD-Discovery page on the CCDC website to learn more about the various components within CSD-Discovery and to discover what’s new in the functionality in the latest CSD release. https://www.ccdc.cam.ac.uk/solutions/csd-discovery/