A complete solution for ligand-receptor docking

The Advantages of Computational Docking

The widespread use of combinatorial chemistry and high-throughput screening (HTS) in the pharmaceutical and biotechnology industries means that large numbers of compounds can now routinely be investigated for biological activity. However, screening large chemical libraries remains an expensive and time-consuming process, with significant rates of both false positives and false negatives.

High-speed computational methods can now enrich the fraction of suitable lead candidates in a chemical database, thereby creating the potential to greatly enhance productivity and dramatically reduce drug development costs. With an ever increasing number of drug discovery projects having access to high-resolution crystal structures of their targets, high-performance ligand-receptor docking is the clear computational strategy of choice to augment and accelerate structure-based drug design.

Complete solution:
Glide offers the full range of speed vs. accuracy options, from the HTVS (high-throughput virtual screening) mode for efficiently enriching million compound libraries, to the SP (standard precision) mode for reliably docking tens to hundreds of thousands of ligands with high accuracy, to the XP (extra precision) mode where further elimination of false positives is accomplished by more extensive sampling and advanced scoring, resulting in even higher enrichment.

Virtual screening:
Glide provides a rational workflow for virtual screening from HTVS to SP to XP, enriching the data at every level such that only an order of magnitude fewer compounds need to be studied at the next higher accuracy level.

Accurate binding mode prediction:
Glide reliably finds the correct binding modes for a large set of test cases. It outperforms other docking programs in achieving lower RMS deviations from native co-crystallized structures.

Universal applicability:
Glide exhibits excellent docking accuracy and high enrichment across a diverse range of receptor types.

Fully prepared databases of purchasable compounds from Enamine, MolPort, MilliporeSigma, and Mcule:
Schrödinger has partnered with Enamine, MilliporeSigma, MolPort and Mcule to provide a Phase database of fragments, lead-like, near drug-like, and drug-like compounds available from Enamine's "Stock Screening Compounds Collection", MilliporeSigma's "Aldrich Market Select", MolPort's "Screening Compound Database", and Mcule's Mcule In Stock Purchasable database, respectively.

Citations and Acknowledgements

Schrödinger Release 2023-4: Glide, Schrödinger, LLC, New York, NY, 2023.

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ö Halgren, T. A.; Murphy, R. B.; Friesner, R. A.; Beard, H. S.; Frye, L. L.; Pollard, W. T.; Banks, J. L., "Glide: A New Approach for Rapid, Accurate Docking and Scoring. 2. Enrichment Factors in Database Screening," J. Med. Chem., 2004, 47, 1750–1759

ö Friesner, R. A.; Banks, J. L.; Murphy, R. B.; Halgren, T. A.; Klicic, J. J.; Mainz, D. T.; Repasky, M. P.; Knoll, E. H.; Shaw, D. E.; Shelley, M.; Perry, J. K.; Francis, P.; Shenkin, P. S., "Glide: A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy," J. Med. Chem., 2004, 47, 1739–1749

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"In silico Predicted Glucose-1-phosphate Uridylyltransferase (GalU) Inhibitors Block a Key Pathway Required for Listeria Virulence"

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"Characterizing the Chemical Space of ERK2 Kinase Inhibitors Using Descriptors Computed from Molecular Dynamics Trajectories"

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"Best Practices of Computer-Aided Drug Discovery: Lessons Learned from the Development of a Preclinical Candidate for Prostate Cancer with a New Mechanism of Action"

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· "Investigating Protein–Peptide Interactions Using the Schrödinger Computational Suite"

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· "A Computational Approach to Enzyme Design: Predicting ω-Aminotransferase Catalytic Activity Using Docking and MM-GBSA Scoring"

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· "A Structure-Based Virtual Screening Approach for Discovery of Covalently Bound Ligands"

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· "Docking covalent inhibitors: A parameter free approach to pose prediction and scoring"

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"The marine-derived sipholenol A-4-O-3′,4′-dichlorobenzoate inhibits breast cancer growth and motility in vitro and in vivo through the suppression of Brk and FAK signaling"

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"Discovery of Thienoquinolone Derivatives as Selective and ATP Non-Competitive CDK5/p25 Inhibitors by Structure-Based Virtual Screening"

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· "Boosting virtual screening enrichments with data fusion: Coalescing hits from two-dimensional fingerprints, shape, and docking"

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"The use of virtual screening and differential scanning fluorimetry for the rapid identification of fragments active against MEK1"

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"Multiple e-pharmacophore modeling combined with high-throughput virtual screening and docking to identify potential inhibitors of β-Secretase(BACE1)"

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"Long-range electrostatic complementarity governs substrate recognition by human chymotrypsin C, a key regulator of digestive enzyme activation"

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"Receptor- and ligand-based study of fullerene analogues: Comprehensive computational approach including quantum-chemical, QSAR and molecular docking simulations"

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"Optimization of peptide hydroxamate inhibitors of insulin-degrading enzyme reveals marked substrate-selectivity"

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· "Improved docking of polypeptides with Glide"

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· "Generation of receptor structural ensembles for virtual screening using binding site shape analysis and clustering"

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· "Exploring protein flexibility: Incorporating structural ensembles from crystal structures and simulation into virtual screening protocols"

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· "Consensus Induced Fit Docking (cIFD): Methodology, validation, and application to the discovery of novel Crm1 inhibitors"

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· "Docking performance of the Glide program as evaluated on the Astex and DUD datasets: A complete set of Glide SP results and selected results for a new scoring function integrating WaterMap and Glide"

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"Trimethylaurintricarboxylic Acid Inhibits Human DNA Methyltransferase 1: Insights From Enzymatic and Molecular Modeling Studies"

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"Homology modeling, docking and structure-based pharmacophore of inhibitors of DNA methyltransferase"

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"A computational approach to design and evaluate enzymatic reaction pathways: application to 1-butanol production from pyruvate"

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"Combined receptor and ligand-based approach to the universal pharmacophore model development for studies of drug blockade to the hERG1 pore domain"

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"Structure-based design of novel boronic acid-based inhibitors of autotaxin"

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· "IDSite: An Accurate Approach to Predict P450-Mediated Drug Metabolism"

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"Theoretical Study on the Redox Cycle of Bovine Glutathione Peroxidase GPx1: pKa Calculations, Docking, and Molecular Dynamics Simulations"

Ali, S. T.; Jahangir, S.; Karamat, S.; Fabian, W. M. F.; Nawara, K.; Kóňa, J., J. Chem. Theory Comput., 2010, 6, 1670–1681

· "Novel Inhibitors of Dengue Virus Methyltransferase: Discovery by in Vitro-Driven Virtual Screening on a Desktop Computer Grid"

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· "Computational Approaches for Fragment-Based and De Novo Design"

Loving, K.; Alberts, I.; Sherman, W., Curr. Top. Med. Chem., 2010, 10, 14-32

"NADH Oxidase Activity of Bacillus subtilis Nitroreductase NfrA1: Insight into its Biological Role"

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"Discovery of Novel Fibroblast Growth Factor Receptor 1 Kinase Inhibitors by Structure-Based Virtual Screening"

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"Discovery of Potent Ligands for Estrogen Receptor β by Structure-Based Virtual Screening"

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"Molecular Docking of Carbohydrate Ligands to Antibodies: Structural Validation against Crystal Structures"

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· "Novel Method for Generating Structure-Based Pharmacophores Using Energetic Analysis"

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· "Energetic analysis of fragment docking and application to structure-based pharmacophore hypothesis generation"

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"Virtual fragment screening: an exploration of various docking and scoring protocols for fragments using Glide"

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"Glucose-based spiro-isoxazolines: A new family of potent glycogen phosphorylase inhibitors"

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"Cis-Configured Aziridines Are New Pseudo-Irreversible Dual-Mode Inhibitors of Candida albicans Secreted Aspartic Protease 2"

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"Combination of Virtual Screening and High Throughput Gene Profiling for Identification of Novel Liver X Receptor Modulators"

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· "Improving database enrichment through ensemble docking"

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"Substitution of Aminomethyl at the Meta-Position Enhances the Inactivation of O(6)-Alkylguanine-DNA Alkyltransferase by O(6)-Benzylguanine"

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"Docking Study Yields Four Novel Inhibitors of the Protooncogene Pim-1 Kinase"

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"1,2,3-Thiadiazole substituted pyrazolones as potent KDR/VEGFR-2 kinase inhibitors"

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"Evaluation of docking programs for predicting binding of Golgi alpha-mannosidase II inhibitors: A comparison with crystallography"

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"Comparative Performance of Several Flexible Docking Programs and Scoring Functions: Enrichment Studies for a Diverse Set of Pharmaceutically Relevant Targets"

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"Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity"

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"The role of tyrosine 177 in human 11β-hydroxysteroid dehydrogenase type 1 in substrate and inhibitor binding: an unlikely hydrogen bond donor for the substrate"

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"Furan-2-ylmethylene thiazolidinediones as novel, potent, and selective inhibitors of phosphoinositide 3-kinase gamma"

Pomel, V.; Klicic, J.; Covini, D.; Church, D.D.; Shaw, J.P.; Roulin, K.; Burgat-Charvillon, F.; Valognes, D.; Camps, M.; Chabert, C.; Gillieron, C.; Françon, B.; Perrin, D.; Leroy, D.; Gretener, D.; Nichols, A.; Vitte, P.A.; Carboni, S.; Rommel, C.; Schwa, J. Med. Chem., 2006, , 3857-3871

· "Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein-Ligand Complexes"

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"Evaluation of library ranking efficacy in virtual screening"

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"Recent Advances in Docking and Scoring"

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· "Importance of Accurate Charges in Molecular Docking: Quantum Mechanical/Molecular Mechanical (QM/MM) Approach"

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"Virtual screening: Gliding to success"

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"Finding More Needles in the Haystack: A Simple and Efficient Method for Improving High-Throughput Docking Results"

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"A Detailed Comparison of Current Docking and Scoring Methods on Systems of Pharmaceutical Relevance"

Perola, E.; Walters, W.P.; Charifson, P.S., Proteins, 2004, 56, 235–249

"Tryptophan 500 and Arginine 707 Define Product and Substrate Active Site Binding in Soybean Lipoxygenase-1"

Ruddat, V. C.; Mogul, R.; Chorny, I.; Chen, C.; Perrin, N.; Whitman, S.; Kenyon, V.; Jacobson, M. P.; Bernasconi, C. F.; Holman, T. R., Biochemistry, 2004, 43, 13063–13071

"Comparative Evaluation of Eight Docking Tools for Docking and Virtual Screening Accuracy"

Kellenberger, E.; Rodrigo, J.; Muller, P.; Rognan, D., Proteins, 2004, 57, 225–242

"Application of Machine Learning To Improve the Results of High-Throughput Docking Against the HIV-1 Protease"

Klon, A. E.; Glick, M.; Davies, J. W., J. Chem. Inf. Comput. Sci., 2004, 44, 2216–2224

"Evaluation of Docking Performance: Comparative Data on Docking Algorithms"

Kontoyianni, M.; McClellan, L. M.; Sokol, G. S., J. Med. Chem., 2004, 47, 558–565

· "Glide: A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy"

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· "Glide: A New Approach for Rapid, Accurate Docking and Scoring. 2. Enrichment Factors in Database Screening"

Halgren, T. A.; Murphy, R. B.; Friesner, R. A.; Beard, H. S.; Frye, L. L.; Pollard, W. T.; Banks, J. L., J. Med. Chem., 2004, 47, 1750–1759

"Validation of Molecular Docking Calculations Involving FGF-1 and FGF-2"

Bytheway, I.; Cochran, S., J. Med. Chem., 2004, 47, 1683-1693

"Synthesis and Discovery of Macrocyclic Polyoxygenated Bis-7-azaindolylmaleimides as a Novel Series of Potent and Highly Selective Glycogen Synthase Kinase-3 Inhibitors"

Kuo, G.-H.; Prouty, C.; DeAngelis, A.; Shen, L.; O'Neill, D. J.; Shah, C.; Connolly, P. J.; Murray, W. V.; Conway, B. R.; Cheung, P.; Westover, L.; Xu, J. Z.; Look, R. A.; Demarest, K. T.; Emanuel, S.; Middleton, S. A.; Jolliffe, L.; Beavers, M. P.; Chen,, J. Med. Chem., 2003, 46, 4021–4031

"Synthesis of Novel Thrombin Inhibitors. Use of Ring-Closing Metathesis Reactions for Synthesis of P2 Cyclopentene- and Cyclohexenedicarboxylic Acid Derivatives"

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"Development and Characterization of Nonpeptidic Small Molecule Inhibitors of the XIAP/Caspase-3 Interaction"

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"Binding site characteristics in structure-based virtual screening: evaluation of current docking tools"

Schulz-Gasch, T; Stahl, M., J. Mol. Mod., 2003, 9, 47–57

"(S)-2-Amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl) propionic Acid, a Potent and Selective Agonist at the GluR5 Subtype of Ionotropic Glutamate Receptors. Synthesis, Modeling, and Molecular Pharmacology"

Brehm, L.; Greenwood, J. R.; Hansen, K. B.; Nielsen, B.; Egebjerg, J.; Stensbol, T. B.; Brauner-Osborne, H.; Slok, F. A.; Kronborg, T. T. A.; Krogsgaard-Larsen, P., J. Med. Chem., 2003, 46, 1350–1358

"Design, Synthesis, and Pharmacology of a Highly Subtype-Selective GluR1/2 Agonist, (RS)-2-Amino-3-(4-chloro-3-hydroxy-5-isoxazolyl)propionic Acid (Cl-HIBO)"

Bjerrum, E. J.; Kristensen, A. S.; Pickering, D. S.; Greenwood, J. R.; Nielsen, B.; Liljefors, T.; Schousboe, A.; Brauner-Osborne, H.; Madsen, U., J. Med. Chem., 2003, 46, 2246–2249

"Stereostructure-Activity Studies on Agonists at the AMPA and Kainate Subtypes of Ionotropic Glutamate Receptors"

Johansen, T. N.; Greenwood, J. R.; Frydenvang, K.; Madsen, U.; Krogsgaard-Larsen, P., Chirality, 2003, 15, 167–179

"Synthesis and SAR of Thrombin Inhibitors Incorporating a Novel 4-Amino-Morpholinone Scaffold: Analysis of X-ray Crystal Structure of Enzyme Inhibitor Complex"

Nilsson, J. W.; Kvarnstrom, I.; Musil, D.; Nilsson, I.; Samulesson, B., J. Med. Chem., 2003, 46, 3985–4001

"Rational Design, Synthesis, and Pharmacological Evaluation of 2-Azanorbornane-3-exo,5-endo-dicarboxylic Acid: A Novel Conformationally Restricted Glutamic Acid Analogue"

Bunch, L.; Liljefors, T.; Greenwood, J. R.; Frydenvang, K.; Brauner-Osborne, H.; Krogsgaard-Larsen, P.; Madsen, U., J. Org. Chem., 2003, 68, 1489–1495

"Selective Agonists at Group II Metabotropic Glutamate Receptors: Synthesis, Stereochemistry, and Molecular Pharmacology of (S)- and (R)-2-Amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl) butyric Acid"

lausen, R. P.; Brauner-Osborne, H.; Greenwood, J. R.; Hermit, M. B.; Stensbol, T. B.; Nielsen, B.; Krogsgaard-Larsen, P., J. Med. Chem., 2002, 45, 4240–4245

"Metal-Dependent Inhibition of HIV-1 Integrase"

Neamati, N.; Lin, Z.; Karki, R. G.; Orr, A.; Cowansage, K.; Strumberg, D.; Pais, G. C. G.; Voigt, J. H.; Nicklaus, M. C.; Winslow, H. E.; Zhao, H.; Turpin, J. A.; Yi, J.; Skalka, A. M.; Burke, T. R., Jr.; Pommier, Y., J. Med. Chem., 2002, 45, 5661–5670

"Solvent Models for Protein-Ligand Binding: Comparison of Implicit Solvent Poisson and Surface Generalized Born Models with Explicit Solvent Simulations"

Zhang, L.Y.; Gallicchio, E.; Friesner, R.A.; Levy, R.M., J. Comput. Chem., 2001, 22, 591–607

Drug-Like Ligand Decoys Set

Schrödinger has made available a set of the ligand decoys used in Glide enrichment studies.

1K Drug-Like Ligand Decoys Set: This collection of ligands was created by selecting 1000 ligands from a one million compound library that were chosen to exhibit "drug-like" properties. Creation and application of the ligand set is presented in the following publications:

Friesner, R. A.; Banks, J. L.; Murphy, R. B.; Halgren, T. A.; Klicic, J. J.; Mainz, D. T.; Repasky, M. P.; Knoll, E. H.; Shaw, D. E.; Shelley, M.; Perry, J. K.; Francis, P.; Shenkin, P. S, "Glide: A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy", J. Med. Chem. 2004, 47, 1739-1749.

Halgren, T. A.; Murphy, R. B.; Friesner, R. A.; Beard, H. S.; Frye, L. L.; Pollard, W. T.; Banks, J. L., "Glide: A New Approach for Rapid, Accurate Docking and Scoring. 2. Enrichment Factors in Database Screening", J. Med. Chem. 2004, 47, 1750-1759.


Last updated 11/17/2009


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