Abstract
A significant prerequisite for computational structure-based drug design is the estimation of the structures of ligand-receptor complexes. For this task, the flexibility of both ligand and receptor backbone is required, but it requires the exploration of an extremely vast conformational space. Here we present a protocol to address the receptor flexibility using complementary strategies and the use of receptor sequence conservation. The method aims to increase the accuracy of predicted ligand orientation in the binding pocket and the receptor-ligand binding affinity. The precision in affinity prediction permits to distinguish between binders and non-binders and to identify binding sites and ligand poses necessary for lead optimization.
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References
Goldsmith, M.-R., Grulke, C.M., Chang, D.T., Transue, T.R., Little, S.B., Rabinowitz, J.R., Tornero-Velez, R.: DockScreen: A Database of In Silico Biomolecular Interactions to Support Computational Toxicology. Dataset Papers in Science 2014 (2014)
Pomerantz, M.M., Li, F., Takeda, D.Y., Lenci, R., Chonkar, A., Chabot, M., Cejas, P., Vazquez, F., Cook, J., Shivdasani, R.A., Bowden, M., Lis, R., Hahn, W.C., Kantoff, P.W., Brown, M., Loda, M., Long, H.W., Freedman, M.L.: The androgen receptor cistrome is extensively reprogrammed in human prostate tumorigenesis. Nat. Genet. 47(11), 1346–1351 (2015)
Lopez, D.H., Fiol-deRoque, M.A., Noguera-Salvà, M.A., Terés, S., Campana, F., Piotto, S., Castro, J.A., Mohaibes, R.J., Escribá, P.V., Busquets, X.: 2-Hydroxy arachidonic acid: a new non-steroidal anti-inflammatory drug. PLoS ONE 8(8), e72052 (2013)
Piotto, S., Concilio, S., Bianchino, E., Iannelli, P., López, D.J., Terés, S., Ibarguren, M., Barceló-Coblijn, G., Martin, M.L., Guardiola-Serrano, F.: Differential effect of 2-hydroxyoleic acid enantiomers on protein (sphingomyelin synthase) and lipid (membrane) targets. Biochim. Biophys. Acta (BBA)-Biomembr. 1838(6), 1628–1637 (2014)
Piotto, S., Concilio, S., Mavelli, F., Iannelli, P.: Computer simulations of natural and synthetic polymers in confined systems. Macromolecular symposia 286(1), 25–33 (2009)
Piotto, S., Trapani, A., Bianchino, E., Ibarguren, M., López, D.J., Busquets, X., Concilio, S.: The effect of hydroxylated fatty acid-containing phospholipids in the remodeling of lipid membranes. Biochim. Biophys. Acta (BBA)- Biomembr. 1838(6), 1509–1517 (2014)
Piotto, S.P., Sessa, L., Concilio, S., Iannelli, P.: YADAMP: yet another database of antimicrobial peptides. Int. J. Antimicrob. Agents 39(4), 346–351 (2012)
Scrima, M., Di Marino, S., Grimaldi, M., Campana, F., Vitiello, G., Piotto, S.P., D’Errico, G., D’Ursi, A.M.: Structural features of the C8 antiviral peptide in a membrane-mimicking environment. Biochim. Biophys. Acta (BBA)- Biomembr. 1838(3), 1010–1018 (2014)
Piotto, S., Nesper, R.: CURVIS: A program to study and analyse crystallographic structures and phase transitions. J. Appl. Crystallogr. 38(1), 223–227 (2005)
Torok, Z., Crul, T., Maresca, B., Schutz, G.J., Viana, F., Dindia, L., Piotto, S., Brameshuber, M., Balogh, G., Peter, M., Porta, A., Trapani, A., Gombos, I., Glatz, A., Gungor, B., Peksel, B., Vigh Jr., L., Csoboz, B., Horvath, I., Vijayan, M.M., Hooper, P.L., Harwood, J.L., Vigh, L.: Plasma membranes as heat stress sensors: from lipid-controlled molecular switches to therapeutic applications. Biochim. Biophys. Acta 1838(6), 1594–1618 (2014)
Crul, T., Toth, N., Piotto, S., Literati-Nagy, P., Tory, K., Haldimann, P., Kalmar, B., Greensmith, L., Torok, Z., Balogh, G., Gombos, I., Campana, F., Concilio, S., Gallyas, F., Nagy, G., Berente, Z., Gungor, B., Peter, M., Glatz, A., Hunya, A., Literati-Nagy, Z., Vigh Jr., L., Hoogstra-Berends, F., Heeres, A., Kuipers, I., Loen, L., Seerden, J.P., Zhang, D., Meijering, R.A., Henning, R.H., Brundel, B.J., Kampinga, H.H., Koranyi, L., Szilvassy, Z., Mandl, J., Sumegi, B., Febbraio, M.A., Horvath, I., Hooper, P.L., Vigh, L.: Hydroximic acid derivatives: pleiotropic HSP co-inducers restoring homeostasis and robustness. Curr. Pharm. Des. 19(3), 309–346 (2013)
Gombos, I., Crul, T., Piotto, S., Gungor, B., Torok, Z., Balogh, G., Peter, M., Slotte, J.P., Campana, F., Pilbat, A.M., Hunya, A., Toth, N., Literati-Nagy, Z., Vigh Jr., L., Glatz, A., Brameshuber, M., Schutz, G.J., Hevener, A., Febbraio, M.A., Horvath, I., Vigh, L.: Membrane-lipid therapy in operation: the HSP co-inducer BGP-15 activates stress signal transduction pathways by remodeling plasma membrane rafts. PLoS ONE 6(12), e28818 (2011)
Vigh, L., Torok, Z., Balogh, G., Glatz, A., Piotto, S., Horvath, I.: Membrane-regulated stress response: a theoretical and practical approach. In: Vigh, L., Csermely, L. (eds.) Molecular Aspects of the Stress Response: Chaperones, Membranes and Networks. Advances in experimental medicine and biology, vol. 594, pp. 114–131. Springer Science + Business Media, New York (2007)
Lange, O.F., Lakomek, N.-A., Farès, C., Schröder, G.F., Glatz, A., Walter, K.F., Becker, S., Meiler, J., Grubmüller, H., Griesinger, C., De Groot, B.L.: Recognition dynamics up to microseconds revealed from an RDC-derived ubiquitin ensemble in solution. Science 320(5882), 1471–1475 (2008)
Mittermaier, A., Kay, L.E.: New tools provide new insights in NMR studies of protein dynamics. Science 312(5771), 224–228 (2006)
Tuffery, P., Derreumaux, P.: Flexibility and binding affinity in protein–ligand, protein–protein and multi-component protein interactions: limitations of current computational approaches. J. Roy. Soc. Interface 9(66), 20–33 (2012)
Chou, K.C.: Biological functions of low-frequency vibrations (phonons). III. Helical structures and microenvironment. Biophys. J. 45(5), 881–889 (1984)
Piotto, S., Biasi, L.D., Concilio, S., Castiglione, A., Cattaneo, G.: GRIMD: distributed computing for chemists and biologists. Bioinformation 10(1), 43–47 (2014)
Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T., Weissig, H., Shindyalov, I.N., Bourne, P.E.: The protein data bank. Nucleic Acids Res. 28(1), 235–242 (2000)
Krieger, E., Vriend, G.: YASARA View - molecular graphics for all devices - from smartphones to workstations. Bioinformatics 30(20), 2981–2982 (2014)
Trott, O., Olson, A.J.: AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 31(2), 455–461 (2010)
Acknowledgments
This work was partially supported by the “Data-Driven Genomic Computing (GenData 2020)” PRIN project (2013–2015), funded by the Italian Ministry of the University and Research (MIUR).
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Sessa, L. et al. (2016). A New Flexible Protocol for Docking Studies. In: Rossi, F., Mavelli, F., Stano, P., Caivano, D. (eds) Advances in Artificial Life, Evolutionary Computation and Systems Chemistry. WIVACE 2015. Communications in Computer and Information Science, vol 587. Springer, Cham. https://doi.org/10.1007/978-3-319-32695-5_11
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DOI: https://doi.org/10.1007/978-3-319-32695-5_11
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