Challenges of docking in large, flexible and promiscuous binding sites
Open accessAbstract
After decades of work, the correct determination of the binding mode of a small molecule into a target protein is still a challenging problem, whose difficulty depends on: (i) the sizes of the binding site and the ligand; (ii) the flexibility of both interacting partners, and (iii) the differential solvation of bound and unbound partners. We have evaluated the performance of standard rigid(receptor)/flexible(ligand) docking approaches with respect to last-generation fully flexible docking methods to obtain reasonable poses in a very challenging case: soluble Epoxide Hydrolase (sEH), a flexible protein showing different binding sites. We found that full description of the flexibility of both protein and ligand and accurate description of solvation leads to significant improvement in the ability of docking to reproduce well known binding modes, and at the same time capture the intrinsic binding promiscuity of the protein.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Flexibility of the molecule is a crucial factor to be considered in most cases.
“Since in most cases flexibility of the molecule is a crucial factor to be considered [177], approaches that tackle this problem have been developed over the years.”
From Computational approaches to therapeutic antibody design: established methods and emerging trends (2020) · cites this paper as [177]
Cites
Comparison of simple potential functions for simulating liquid water
Jorgensen, W. L., Chandrasekhar, J., Madura, J., Impey, R., & Klein, M. (1983) · The Journal of Chemical Physics · doi:10.1063/1.445869 · Cited by 38,335 · see citing works
Ryckaert, J., Ciccotti, G., & Berendsen, H. (1977) · Journal of Computational Physics · doi:10.1016/0021-9991(77)90098-5 · Cited by 19,525 · see citing works
Development and testing of a general amber force field
Wang, J.-M., Wolf, R., Caldwell, J., Kollman, P., & Case, D. (2004) · Journal of Computational Chemistry · doi:10.1002/jcc.20035 · Cited by 18,318 · see citing works
Friesner, R. A., Banks, J. L., Murphy, R. B., Halgren, T. A., Klicic, J. J., Mainz, D. T., Repasky, M. P., Knoll, E. H., Shelley, M., Perry, J. K., et al. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm0306430 · Cited by 10,057 · see citing works
PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data.
Roe, D., & Cheatham, T. (2013) · Journal of Chemical Theory and Computation · doi:10.1021/ct400341p · Cited by 6,969 · see citing works
Sastry, G. M., Adzhigirey, M., Day, T., Annabhimoju, R., & Sherman, W. (2013) · Journal of Computer-Aided Molecular Design · doi:10.1007/s10822-013-9644-8 · Cited by 6,130 · see citing works
Halgren, T. A., Murphy, R. B., Friesner, R. A., Beard, H. S., Frye, L. L., Pollard, W. T., & Banks, J. L. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm030644s · Cited by 5,280 · see citing works
Docking and scoring in virtual screening for drug discovery: methods and applications
Kitchen, D. B., Decornez, H. Y., Furr, J. R., & Bajorath, J. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1549 · Cited by 4,245 · see citing works
Kaminski, G. A., Friesner, R. A., Tirado‐Rives, J., & Jorgensen, W. L. (2001) · The Journal of Physical Chemistry B · doi:10.1021/jp003919d · Cited by 4,077 · see citing works
Principles of early drug discovery
Hughes, J., Rees, S., Kalindjian, S., & Philpott, K. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.01127.x · Cited by 2,859 · see citing works
Onufriev, A., Bashford, D., & Case, D. A. (2004) · Proteins: Structure, Function, and Bioinformatics · doi:10.1002/prot.20033 · Cited by 2,507 · see citing works
Computational Methods in Drug Discovery
Sliwoski, G. R., Kothiwale, S., Meiler, J., & Lowe, E. W. (2013) · Pharmacological Reviews · doi:10.1124/pr.112.007336 · Cited by 2,226 · see citing works
Novel procedure for modeling ligand/receptor induced fit effects.
Sherman, W., Day, T., Jacobson, M., Friesner, R., & Farid, R. (2006) · Journal of Medicinal Chemistry · doi:10.1021/jm050540c · Cited by 1,998 · see citing works
Direct evaluation of thermal fluctuations in proteins using a single-parameter harmonic potential
Bahar, İ., Atılgan, A. R., & Erman, B. (1997) · Folding and Design · doi:10.1016/s1359-0278(97)00024-2 · Cited by 1,377 · see citing works
Theoretical Methods for the Description of the Solvent Effect in Biomolecular Systems
Orozco, M., & Luque, F. J. (2000) · Chemical Reviews · doi:10.1021/cr990052a · Cited by 628 · see citing works
How Does a Drug Molecule Find Its Target Binding Site?
Shan, Y., Kim, E. T., Eastwood, M. P., Dror, R. O., Seeliger, M. A., & Shaw, D. E. (2011) · Journal of the American Chemical Society · doi:10.1021/ja202726y · Cited by 614 · see citing works
Anton, a special-purpose machine for molecular dynamics simulation
Shaw, D., Deneroff, M. M., Dror, R., Kuskin, J., Larson, R. H., Salmon, J., Young, C., Batson, B., Bowers, K., Chao, J. C., et al. (2008) · CACM · doi:10.1145/1364782.1364802 · Cited by 588 · see citing works
RosettaLigand Docking with Full Ligand and Receptor Flexibility
Davis, I., & Baker, D. A. (2008) · Journal of Molecular Biology · doi:10.1016/j.jmb.2008.11.010 · Cited by 438 · see citing works
Target Flexibility: An Emerging Consideration in Drug Discovery and Design
Cozzini, P., Kellogg, G. E., Spyrakis, F., Abraham, D. J., Costantino, G., Emerson, A. P. J., Fanelli, F., Gohlke, H., Kuhn, L. A., Morris, G. M., et al. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm800562d · Cited by 312 · see citing works
Shen, H. C., & Hammock, B. D. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm201468j · Cited by 231 · see citing works
PELE: Protein Energy Landscape Exploration. A Novel Monte Carlo Based Technique
Borrelli, K. W., Vitalis, A., Alcantara, R., & Guallar, V. (2005) · Journal of Chemical Theory and Computation · doi:10.1021/ct0501811 · Cited by 229 · see citing works
FiberDock: Flexible induced‐fit backbone refinement in molecular docking
Mashiach, E., Nussinov, R., & Wolfson, H. J. (2009) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.22668 · Cited by 187 · see citing works
Good, A. C., & Oprea, T. I. (2008) · Journal of Computer-Aided Molecular Design · doi:10.1007/s10822-007-9167-2 · Cited by 180 · see citing works
Publisher, B. S. P. B. S. (2006) · Current Protein and Peptide Science · doi:10.2174/138920306778559386 · Cited by 178 · see citing works
An Integrated Suite of Fast Docking Algorithms
Mashiach, E., Schneidman-Duhovny, D., Peri, A., Shavit, Y., Nussinov, R., & Wolfson, H. (2010) · Proteins: Structure, Function, and Bioinformatics · doi:10.1002/prot.22790 · Cited by 141 · see citing works
Edman, K., Hosseini, A., Bjursell, M. K., Aagaard, A., Wissler, L., Gunnarsson, A., Kaminski, T. P., Köhler, C., Bäckström, S., Jensen, T. J., et al. (2015) · Structure · doi:10.1016/j.str.2015.09.012 · Cited by 105 · see citing works
Gelpí, J. L., Kalko, S. G., Barril, X., Cirera, J., de la Cruz, X., Luque, F. J., & Orozco, M. (2001) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.1159 · Cited by 98 · see citing works
Rapid Flexible Docking Using a Stochastic Rotamer Library of Ligands
Ding, F., Yin, S., & Dokholyan, N. V. (2010) · Journal of Chemical Information and Modeling · doi:10.1021/ci100218t · Cited by 90 · see citing works
Flexible receptor docking for drug discovery
Wong, C. F. (2015) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2015.1078308 · Cited by 75 · see citing works
Ensemble Docking from Homology Models
Novoa, E. M., de Pouplana, L. R., Barril, X., & Orozco, M. (2010) · Journal of Chemical Theory and Computation · doi:10.1021/ct100246y · Cited by 67 · see citing works
Successful generation of structural information for fragment-based drug discovery
Öster, L., Tapani, S., Xue, Y., & Käck, H. (2015) · Drug Discovery Today · doi:10.1016/j.drudis.2015.04.005 · Cited by 64 · see citing works
Borrelli, K. W., Cossins, B. P., & Guallar, V. (2009) · Journal of Computational Chemistry · doi:10.1002/jcc.21409 · Cited by 64 · see citing works
Takahashi, R., Gil, V., & Guallar, V. (2014) · Journal of Chemical Theory and Computation · doi:10.1021/ct400678g · Cited by 45 · see citing works
Computational Prediction of HIV-1 Resistance to Protease Inhibitors
Hosseini, A., Alibés, A., Noguera-Julián, M., Gil, V., Paredes, R., Soliva, R., Orozco, M., & Guallar, V. (2016) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.5b00667 · Cited by 29 · see citing works
Inhibition of soluble epoxide hydrolase by fulvestrant and sulfoxides
Morisseau, C. H. P., Pakhomova, S., Hwang, S. H., Newcomer, M. E., & Hammock, B. D. (2013) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2013.04.083 · Cited by 17 · see citing works
Fast Atomistic Molecular Dynamics Simulations from Essential Dynamics Samplings
Carrillo, O., Laughton, C. A., & Orozco, M. (2012) · Journal of Chemical Theory and Computation · doi:10.1021/ct2007296 · Cited by 12 · see citing works
Chaudhuri, R., Carrillo, O., Laughton, C. A., & Orozco, M. (2012) · Journal of Chemical Theory and Computation · doi:10.1021/ct300223c · Cited by 11 · see citing works
New Monte Carlo Based Technique To Study DNA–Ligand Interactions
de Vaca, I. C., Lucas, M. F., & Guallar, V. (2015) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.5b00838 · Cited by 9 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Computational approaches to therapeutic antibody design: established methods and emerging trends
Norman, R. A., Ambrosetti, F., Bonvin, A. M. J. J., Colwell, L. J., Kelm, S., Kumar, S., & Krawczyk, K. (2020) · Briefings in Bioinformatics · doi:10.1093/bib/bbz095 · Cited by 219 · see citing works
“Since in most cases flexibility of the molecule is a crucial factor to be considered [177], approaches that tackle this problem have been developed over the years.”
BackgroundLotz, S., & Dickson, A. (2018) · Journal of the American Chemical Society · doi:10.1021/jacs.7b08572 · Cited by 126 · see citing works
Computational tools for enzyme improvement: why everyone can – and should – use them
Ebert, M. C. C. J. C., & Pelletier, J. N. (2017) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2017.01.021 · Cited by 110 · see citing works
Modeling Antibody-Antigen Complexes by Information-Driven Docking
Ambrosetti, F., Jiménez‐García, B., Roel‐Touris, J., & Bonvin, A. M. J. J. (2019) · Structure · doi:10.1016/j.str.2019.10.011 · Cited by 97 · see citing works
Adaptive simulations, towards interactive protein-ligand modeling
Lecina, D., Gilabert, J. F., & Guallar, V. (2017) · Scientific Reports · doi:10.1038/s41598-017-08445-5 · Cited by 79 · see citing works
Computational structure‐based drug design: Predicting target flexibility
Iglesias, J., Saen‐oon, S., Soliva, R., & Guallar, V. (2018) · Wiley Interdisciplinary Reviews Computational Molecular Science · doi:10.1002/wcms.1367 · Cited by 65 · see citing works
Computational Enzyme Engineering Pipelines for Optimized Production of Renewable Chemicals
Scherer, M., Fleishman, S. J., Jones, P. R., Dandekar, T., & Bencúrová, E. (2021) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2021.673005 · Cited by 33 · see citing works
Substrate-Specific Screening for Mutational Hotspots Using Biased Molecular Dynamics Simulations
Ebert, M. C. C. J. C., Espinola, J. G., Lamoureux, G., & Pelletier, J. N. (2017) · ACS Catalysis · doi:10.1021/acscatal.7b02634 · Cited by 23 · see citing works
Kotev, M. I., Pascual, R., Almansa, C., Guallar, V., & Soliva, R. (2018) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.8b00347 · Cited by 20 · see citing works
Gazzillo, E., Terracciano, S., Ruggiero, D., Potenza, M., Chini, M. G., Lauro, G., Fischer, K., Hofstetter, R. K., Giordano, A., Werz, O., et al. (2022) · Molecules · doi:10.3390/molecules27123866 · Cited by 12 · see citing works
Lee, K. S. S., Henriksen, N. M., Ng, C., Yang, J., Jia, W., Morisseau, C. H. P., Andaya, A., Gilson, M. K., & Hammock, B. D. (2016) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2016.10.017 · Cited by 9 · see citing works
Monte Carlo simulations using PELE to identify a protein–protein inhibitor binding site and pose
Díaz, L., Soler, D., Tresadern, G., Buyck, C., Pérez‐Benito, L., Saen‐oon, S., Guallar, V., & Soliva, R. (2020) · RSC Advances · doi:10.1039/d0ra01127d · Cited by 8 · see citing works
In silico Techniques for Prospecting and Characterizing Monoclonal Antibodies
Manieri, T. M., Magalhães, C. G., Takata, D. Y., Batalha-Carvalho, J. V., & Moro, A. M. (2020) · IntechOpen eBooks · doi:10.5772/intechopen.94366 · Cited by 7 · see citing works
Fine tuning for success in structure-based virtual screening
Pihan, É., Kotev, M. I., Rabal, O., Beato, C., & Gonzalez, C. D. (2021) · Journal of Computer-Aided Molecular Design · doi:10.1007/s10822-021-00431-4 · Cited by 6 · see citing works
Șterbuleac, D., & Maniu, C. L. (2018) · Molecular Informatics · doi:10.1002/minf.201700142 · Cited by 6 · see citing works
Integrating Hydrogen Exchange with Molecular Dynamics for Improved Ligand Binding Predictions
Walters, B. T., Patapoff, A. W., Kiefer, J. R., Wu, P., & Wang, W. (2025) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.5c00397 · Cited by 4 · see citing works
Molecular Dynamics and Other HPC Simulations for Drug Discovery
Kotev, M. I., & Gonzalez, C. D. (2023) · Methods in molecular biology · doi:10.1007/978-1-0716-3449-3_12 · Cited by 4 · see citing works
Yadav, A. J., Bhagat, K., Sharma, A., & Padhi, A. K. (2025) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2024.10.011 · Cited by 3 · see citing works
Information-driven modelling of antibody–antigen complexes
Ambrosetti, F., Jiménez-García, B., Roel-Touris, J., & Bonvin, A. M. J. J. (2019) · SSRN Electronic Journal · doi:10.2139/ssrn.3362436 · Cited by 2 · see citing works
Codony, S., Jora, B., Santos-Caballero, M., Qiu, Q., Calvó‐Tusell, C., Escriche, C., Turcu, A. L., Prischi, F., Bartra, C., Val, C., et al. (2025) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756366.2025.2574990 · Cited by 2 · see citing works
Chelouati, T., Lafraxo, S., Metouekel, A., Messkini, M., Chebaibi, S.-E., Moussaoui, A. E., Barnossi, A. E., Alyami, E. M., Alghamdi, O. A., Jardan, Y. A. B., et al. (2026) · Food Science & Nutrition · doi:10.1002/fsn3.71878 · Cited by 2 · see citing works
Divergent PXR function in seals: Endocrine adaptation or functional loss?
Amorim, I., Oliveira, D., Castro, L. F. C., Ruivo, R., & Lopes‐Marques, M. (2026) · Environmental Toxicology and Pharmacology · doi:10.1016/j.etap.2026.105165 · Cited by 1 · see citing works
Recent PELE Developments and Applications in Drug Discovery Campaigns
Puch-Giner, I., Molina, A., Municoy, M., Perez‐Lopez, C., & Guallar, V. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232416090 · Cited by 1 · see citing works
Designing Antiviral Substances Targeting the Ebola Virus Viral Protein 24
Dapiaggi, F., Pieraccini, S., Potenza, D., Vasile, F., & Podlipnik, Č. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-814966-9.00009-3 · Cited by 1 · see citing works
Phong, N. V., Vinh, L. B., Anh, H. L. T., Lim, S. D., & Yang, S. Y. (2026) · Steroids · doi:10.1016/j.steroids.2026.109854
- Authors
- Kotev, M., Soliva, R., & Orozco, M.
- Affiliations
- Institute for Research in Biomedicine (ES)
- Barcelona Supercomputing Center (ES)
- Corresponding author
- Orozco, Modesto
- Venue
- Bioorganic & Medicinal Chemistry
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 24
- Issue
- 20
- Pages
- 4961-4969
- ISSN
- 0968-0896 (ISSN-L)
- OpenAlex
- W2508448504
- Cited by
- 25
- References
- 38
- Citations by year
- 2026: 3 · 2025: 3 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 4 · 2018: 4 · 2017: 3 · 2016: 1
- FWCI
- 3.68
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- Bioorganic & Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (acceptedVersion, cc-by-nc-nd)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (acceptedVersion, other-oa)
- RECERCAT (Consorci de Serveis Universitaris de Catalunya) (acceptedVersion, other-oa)
- UPCommons institutional repository (Universitat Politècnica de Catalunya) (submittedVersion, public-domain)
- Funders
- Fundació Marató TV3
- H2020
- MINECO (BIO2015/64802-R)
- ICREA
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Keywords
- molecular docking, binding site flexibility, binding promiscuity, solvation effects, soluble epoxide hydrolase, protein-ligand binding mode, ligand flexibility
- MeSH terms
- Binding Sites, Epoxide Hydrolases, Humans, Ligands, Molecular Structure, Small Molecule Libraries, Molecular Docking Simulation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
