September 2011, 3:32,
Open Access This content is freely available online to anyone, anywhere at any time.
Date: 20 Sep 2011
PubChem3D: a new resource for scientists
PubChem is an open repository for small molecules and their experimental biological activity. PubChem integrates and provides search, retrieval, visualization, analysis, and programmatic access tools in an effort to maximize the utility of contributed information. There are many diverse chemical structures with similar biological efficacies against targets available in PubChem that are difficult to interrelate using traditional 2-D similarity methods. A new layer called PubChem3D is added to PubChem to assist in this analysis.
PubChem generates a 3-D conformer model description for 92.3% of all records in the PubChem Compound database (when considering the parent compound of salts). Each of these conformer models is sampled to remove redundancy, guaranteeing a minimum (non-hydrogen atom pair-wise) RMSD between conformers. A diverse conformer ordering gives a maximal description of the conformational diversity of a molecule when only a subset of available conformers is used. A pre-computed search per compound record gives immediate access to a set of 3-D similar compounds (called "Similar Conformers") in PubChem and their respective superpositions. Systematic augmentation of PubChem resources to include a 3-D layer provides users with new capabilities to search, subset, visualize, analyze, and download data.
A series of retrospective studies help to demonstrate important connections between chemical structures and their biological function that are not obvious using 2-D similarity but are readily apparent by 3-D similarity.
The addition of PubChem3D to the existing contents of PubChem is a considerable achievement, given the scope, scale, and the fact that the resource is publicly accessible and free. With the ability to uncover latent structure-activity relationships of chemical structures, while complementing 2-D similarity analysis approaches, PubChem3D represents a new resource for scientists to exploit when exploring the biological annotations in PubChem.
Bolton EE, Wang Y, Thiessen PA, Bryant SH: PubChem: integrated platform of small molecules and biological activities. In Annual Reports in Computational Chemistry. Volume 4. Edited by: Ralph AW, David CS. Elsevier; 2008:217–241.
Wang YL, Xiao JW, Suzek TO, Zhang J, Wang JY, Bryant SH: PubChem: a public information system for analyzing bioactivities of small molecules. Nucleic Acids Res 2009, 37:W623-W633.CrossRef
Wang YL, Bolton E, Dracheva S, Karapetyan K, Shoemaker BA, Suzek TO, Wang JY, Xiao JW, Zhang J, Bryant SH: An overview of the PubChem BioAssay resource. Nucleic Acids Res 2010, 38:D255-D266.CrossRef
Sayers EW, Barrett T, Benson DA, Bolton E, Bryant SH, Canese K, Chetvernin V, Church DM, DiCuccio M, Federhen S, et al.: Database resources of the National Center for Biotechnology Information. Nucleic Acids Res 2011, 39:D38-D51.CrossRef
PubChem3D Thematic Series [http://www.jcheminf.com/series/pubchem3d]
Bolton EE, Kim S, Bryant SH: PubChem3D: conformer generation. J Cheminformatics 2011, 3:4.CrossRef
Bolton EE, Kim S, Bryant SH: PubChem3D: diversity of shape. J Cheminformatics 2011, 3:9.CrossRef
Bolton EE, Kim S, Bryant SH: PubChem3D: similar conformers. J Cheminformatics 2011, 3:13.CrossRef
Kim S, Bolton EE, Bryant SH: PubChem3D: shape compatibility filtering using molecular shape quadrupoles. J Cheminformatics 2011, 3:25.CrossRef
Kim S, Bolton EE, Bryant SH: PubChem3D: biologically relevant 3-D similarity. J Cheminformatics 2011, 3:26.CrossRef
Grant JA, Pickup BT: A Gaussian description of molecular shape. J Phys Chem 1995, 99:3503–3510.CrossRef
Grant JA, Gallardo MA, Pickup BT: A fast method of molecular shape comparison: a simple application of a Gaussian description of molecular shape. J Comput Chem 1996, 17:1653–1666.CrossRef
Grant JA, Pickup BT: Gaussian shape methods. In Computer Simulation of Biomolecular Systems. Edited by: van Gunsteren WF, Weiner PK, Wilkinson AJ. Dordrecht: Kluwer Academic Publishers; 1997:150–176.
ROCS - Rapid Overlay of Chemical Structures, Version 2.2 OpenEye Scientific Software, Inc.: Santa Fe, NM; 2006.
ShapeTK - C++, Version 1.8.0 OpenEye Scientific Software, Inc.: Santa Fe, NM; 2010.
Meanwell NA: Synopsis of some recent tactical application of bioisosteres in drug design. J Med Chem 2011, 54:2529–2591.CrossRef
Nicholls A, McGaughey GB, Sheridan RP, Good AC, Warren G, Mathieu M, Muchmore SW, Brown SP, Grant JA, Haigh JA, et al.: Molecular shape and medicinal chemistry: a perspective. J Med Chem 2010, 53:3862–3886.CrossRef
Mohan V, Gibbs AC, Cummings MD, Jaeger EP, DesJarlais RL: Docking: successes and challenges. Curr Pharm Design 2005, 11:323–333.CrossRef
Simmons KJ, Chopra I, Fishwick CWG: Structure-based discovery of antibacterial drugs. Nat Rev Microbiol 2010, 8:501–510.CrossRef
Andricopulo AD, Salum LB, Abraham DJ: Structure-based drug design strategies in medicinal chemistry. Curr Top Med Chem 2009, 9:771–790.CrossRef
van Montfort RLM, Workman P: Structure-based design of molecular cancer therapeutics. Trends Biotechnol 2009, 27:315–328.CrossRef
Sun H, Scott DO: Structure-based drug metabolism predictions for drug design. Chem Biol Drug Des 2010, 75:3–17.CrossRef
Kuntz ID: Structure-based strategies for drug design and discovery. Science 1992, 257:1078–1082.CrossRef
Halgren TA: Merck molecular force field. 1. Basis, form, scope, parameterization, and performance of MMFF94. J Comput Chem 1996, 17:490–519.CrossRef
Halgren TA: Merck molecular force field. 2. MMFF94 van der Waals and electrostatic parameters for intermolecular interactions. J Comput Chem 1996, 17:520–552.CrossRef
Halgren TA: MMFF VI. MMFF94s option for energy minimization studies. J Comput Chem 1999, 20:720–729.CrossRef
OMEGA, Version 2.0 OpenEye Scientific Software, Inc.: Santa Fe, NM; 2006.
OMEGA, Version 2.1 OpenEye Scientific Software, Inc.: Santa Fe, NM; 2006.
OMEGA, Version 2.2 OpenEye Scientific Software, Inc.: Santa Fe, NM; 2007.
OMEGA, Version 2.3 OpenEye Scientific Software, Inc.: Santa Fe, NM; 2008.
OMEGA, Version 2.4 OpenEye Scientific Software, Inc.: Santa Fe, NM; 2009.
Musafia B, Senderowitz H: Biasing conformational ensembles towards bioactive-like conformers for ligand-based drug design. Expert Opin Drug Discov 2010, 5:943–959.CrossRef
Hawkins PCD, Skillman AG, Warren GL, Ellingson BA, Stahl MT: Conformer generation with OMEGA: algorithm and validation using high quality structures from the Protein Databank and Cambridge Structural Database. J Chem Inf Model 2010, 50:572–584.CrossRef
Sadowski J, Bostrom J: MIMUMBA revisited: Torsion angle rules for conformer generation derived from X-ray structures. J Chem Inf Model 2006, 46:2305–2309.CrossRef
Bostrom J: Reproducing the conformations of protein-bound ligands: a critical evaluation of several popular conformational searching tools. J Comput Aided Mol Des 2001, 15:1137–1152.CrossRef
OEChem, Version 1.7.4 OpenEye Scientific Software, Inc.: Santa Fe, NM; 2010.
Mills JEJ, Dean PM: Three-dimensional hydrogen-bond geometry and probability information from a crystal survey. J Comput Aided Mol Des 1996, 10:607–622.CrossRef
Szybki TK, Version 1.5.0 OpenEye Scientific Software, Inc.: Santa Fe, NM; 2010.
Barnard JM, Downs GM: Clustering of chemical structures on the basis of two-dimensional similarity measures. J Chem Inf Comput Sci 1992, 32:644–649.CrossRef
Lajiness MS, Johnson MA, Maggiora GM: Implementing drug screening programs using molecular similarity methods. Prog Clin Biol Res 1989, 291:173–176.
Fontaine F, Bolton E, Borodina Y, Bryant SH: Fast 3D shape screening of large chemical databases through alignment-recycling. Chem Cent J 2007, 1:12.CrossRef
Mansfield ML, Covell DG, Jernigan RL: A new class of molecular shape descriptors. 1. Theory and properties. J Chem Inf Comput Sci 2002, 42:259–273.CrossRef
Entrez Programming Utilities Help [http://www.ncbi.nlm.nih.gov/books/NBK25501]
Hull D, Wolstencroft K, Stevens R, Goble C, Pocock MR, Li P, Oinn T: Taverna: a tool for building and running workflows of services. Nucleic Acids Res 2006, 34:W729-W732.CrossRef
Pipeline Pilot, Version 8.5 Accelrys, Inc.: San Diego, CA; 2011.
Chan X, Brown B, Hedrick M, Rascon J, Millan JL, Sergienko E, Roth G, Reddy S, Dad S, Chung TDY, et al.: HTS identification of compounds activating TNAP at an intermediate concentration of phosphate acceptor detected in luminescent assay. In Probe Reports from the NIH Molecular Libraries Program. Bethesda, MD: National Center for Biotechnology Information; 2010. 2011/03/25 edition
Medical Subject Headings [http://www.ncbi.nlm.nih.gov/mesh]
- PubChem3D: a new resource for scientists
- Open Access
- Available under Open Access This content is freely available online to anyone, anywhere at any time.
Journal of Cheminformatics
- Online Date
- September 2011
- Online ISSN
- Chemistry Central
- Additional Links
- Author Affiliations
- 1. National Institutes of Health, Department of Health and Human Services, National Center for Biotechnology Information, National Library of Medicine, 8600 Rockville Pike, Bethesda, MD, 20894, USA