CONSTRUCTION AND RETROSPECTIVE VALIDATION OF STRUCTURE-BASED VIRTUAL SCREENING PROTOCOLS TO IDENTIFY POTENT LIGANDS FOR HUMAN ADRENERGIC BETA-2 RECEPTOR

Enade Perdana Istyastono, Dewi Setyaningsih

Abstract


Adrenergic Beta-2 Receptor (ADRB2) is a member of G-protein coupled receptors family, which has served as targets for more than 30% of top-selling drugs in the market. Recently, an enhanced dataset of ligands and decoys for ADRB2 has publicly available. However, the original retrospective structure-based virtual screening campaign accompanying the dataset showed relatively poor quality with enrichment factor of true positives at 1% false positives (EF1%)value of 3.9. In this article, the construction and retrospective validation of a structure-based virtual screening protocol by employing PLANTS1.2 as the molecular docking software and PyPLIF as an alternative post docking scoring functions are presented. The results show that the developed protocols have better quality compared the original structure-based virtual screening with EF1% values of 24.24 and 8.22 by using ChemPLP from PLANTS1.2 and by using Tc-PLIF from PyPLIF, respectively. Further investigation by performing systematic filtering resulted in the identification of D113, S203, and N293 as molecular determinants in ADRB2-ligand binding.

Key words: Structure-based virtual screening, molecular docking, adrenergic beta-2 receptor, protein-ligand interaction fingerprinting, molecular determinants


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References


Ballesteros, JA., Shi, L., Javitch, JA., 2001, Structural mimicry in G protein-coupled receptors: Implications of the high-resolution structure of rhodopsin for structure-function analysis of rhodopsin-like receptors, Mol. Pharmacol., 60,1-19.

Carlsson J., Coleman RG., Setola V., Irwin JJ., Fan H., Schlessinger A., Sali A., Roth BL., Shoichet BK., 2011, Ligand discovery from a dopamine D3 receptor homology model and crystal structure. Nat. Chem. Biol., 7, 769–778.

Carlsson J., Yoo L., Gao, Z., Irwin JJ., Shoichet BK., Jacobson KA., 2010, Structure-based discovery of A2A adenosine receptor ligands. J. Med. Chem. 53, 3748–3755.

Cherezov V., Rosenbaum DM., Hanson MA., Rasmussen SGF., Thian FS., Kobilka TS., Choi H., Kuhn P., Weis WI., Kobilka, BK., Stevens RC., 2007, High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor. Science, 318, 1258–1265.

Chien EYT., Liu W., Zhao Q., Katritch V., Han GW., Hanson MA., Shi L., Newman AH., Javitch JA., Cherezov V., Stevens RC., 2010, Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science, 330, 1091–1095.

De Graaf C., Kooistra AJ., Vischer HF., Katritch V., Kuijer M., Shiroishi M., Iwata S., Shimamura T., Stevens RC., de Esch IJP., Leurs R., 2011a, Crystal structure-based virtual screening for fragment-like ligands of the human histamine H1 receptor. J. Med. Chem., 54, 8195–8206.

De Graaf C., Rein C., Piwnica D., Giordanetto F., Rognan D., 2011b, Structure-based discovery of allosteric modulators of two related class B G-protein-coupled receptors. ChemMedChem, 6, 2159–2169.

De Graaf C., Rognan, D., 2008, Selective structure-based virtual screening for full and partial agonists of the β2 adrenergic receptor, J. Med. Chem., 51, 4978–4985.

Elling, CE., Thirstrup, K., Holst, B., Schwartz, TW., 1999, Conversion of agonist site to metal-ion chelator site in the β2-adrenergic receptor, Proc. Natl. Acad. Sci. U S A., 96, 12322-12327.

Gouldson, PR., Snell, CR., Reynolds, CA., 1997, A new approach to docking in the β2-adrenergic receptor that exploits the domain structure of G-protein-coupled receptors, J. Med. Chem., 40, 3871-3886.

Istyastono EP., de Graaf C., de Esch IJP., Leurs R., 2011a, Molecular determinants of selective agonist and antagonist binding to the histamine H4 receptor. Curr. Top. Med. Chem., 11, 661–679.

Istyastono EP., Nijmeijer S., Lim HD., van de Stolpe A., Roumen L., Kooistra AJ., Vischer HF., de Esch IJP., Leurs R., de Graaf, C., 2011b, Molecular determinants of ligand binding modes in the histamine H4 receptor: Linking ligand-based three-dimensional quantitative structure−activity relationship (3D-QSAR) models to in silico guided receptor mutagenesis studies. J. Med. Chem., 54, 8136–8147.

Jaakola V., Griffith MT., Hanson MA., Cherezov V., Chien EYT., Lane JR., Ijzerman AP., Stevens RC., 2008, The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist. Science, 322, 1211–1217.

Katritch V., Jaakola V., Lane JR., Lin J., Ijzerman AP., Yeager M., Kufareva I., Stevens RC., Abagyan R., 2010, Structure-based discovery of novel chemotypes for adenosine A2A receptor antagonists. J. Med. Chem. 53, 1799–1809.

Klabunde T., Hessler G., 2002, Drug design strategies for targeting G-protein-coupled receptors, ChemBioChem, 3, 928–944.

Kolb P., Rosenbaum DM., Irwin JJ., Fung JJ., Kobilka BK., Shoichet BK., 2009, Structure-based discovery of β2-adrenergic receptor ligands. Proc. Natl. Acad. Sci. U. S. A., 106, 6843–6848.

Korb O., Stützle T., Exner TE., 2009, Empirical scoring functions for advanced protein-ligand docking with PLANTS. J. Chem. Inf. Model., 49, 84–96.

Liapakis, G., Ballesteros, JA., Papachristou, S., Chan, WC., Chen, X., Javitch, JA., 2000, The forgotten serine. A critical role for Ser-2035.42 in ligand binding to and activation of the β2-adrenergic receptor, J. Biol. Chem., 275, 37779-37788.

Lill, MA., Danielson, ML., 2011, Computer-aided drug design platform using PyMOL, J. Comput. Aided Mol. Des., 25, 13–19.

Marcou G., Rognan D., 2007, Optimizing fragment and scaffold docking by use of molecular interaction fingerprints. J. Chem. Inf. Model., 47, 195–207.

Mysinger MM., Carchia M., Irwin JJ., Shoichet BK., 2012, Directory of useful decoys, enhanced (DUD-E): Better ligands and decoys for better benchmarking. J. Med. Chem. 55, 6582–6594.

O’Boyle, NM., Banck, M., James, CA., Morley, C., Vandermeersch, T., Hutchison, GR., 2011, Open Babel: An open chemical toolbox, J. Cheminform., 3, 33.

R Development Core Team, 2008, R: A Language and Environment for Statistical Computing, Vienna, http://www.r-project.org.

Radifar M., Yuniarti N., Istyastono EP., 2013a, PyPLIF: Python-based protein-ligand interaction fingerprinting, Bioinformation, 9, 325–328.

Radifar M., Yuniarti N., Istyastono EP., 2013b, PyPLIF-assisted redocking indomethacin-(R)-α-ethyl-ethanolamide into cyclooxygenase-1. Indo. J. Chem. 13, 283–286.

Rasmussen, SG., Choi, HJ., Fung, JJ., Pardon, E., Casarosa, P., Chae, PS., Devree, BT., Rosenbaum, DM., Thian, FS., Kobilka, TS., Schnapp, A., Konetzki, I., Sunahara, RK., Gellman, SH., Pautsch, A., Steyaert, J., Weis, WI., Kobilka, BK., 2011, Structure of a nanobody-stabilized active state of the β2 adrenoceptor, Nature, 469, 175-180.

Sato, T., Kobayashi, H., Nagao, T., Kurose, H., 1999, Ser203 as well as Ser204 and Ser207 in fifth transmembrane domain of the human β2-adrenoceptor contributes to agonist binding and receptor activation, Br. J. Pharmacol., 128, 272-274.

Seifert MHJ., 2009, Targeted scoring functions for virtual screening. Drug Discov. Today, 14, 562–569.

Setyaningsih D., Radifar M., Murti YB., Istyastono EP., 2013, Construction of in silico structure-based screening tools to study the oxidative metabolites formation of curcumin by human cytochrome 450 3A4. Indonesian J. Pharm., 24, 75–85.

Shimamura T., Shiroishi M., Weyand S., Tsujimoto H., Winter G., Katritch V., Abagyan R., Cherezov V., Liu W., Han GW., Kobayashi T., Stevens RC., Iwata S., 2011, Structure of the human histamine H1 receptor complex with doxepin. Nature, 475, 65–70.

Shin N., Coates E., Murgolo NJ., Morse KL., Bayne M., Strader CD., Monsma FJ., 2002, Molecular modeling and site-specific mutagenesis of the histamine-binding site of the histamine H4 receptor. Mol. Pharmacol., 62, 38–47.

Sirci F., Istyastono EP., Vischer HF., Kooistra AJ., Nijmeijer S., Kuijer M., Wijtmans M., Mannhold R., Leurs R., de Esch IJP., de Graaf C., 2012, Virtual fragment screening: Discovery of histamine H3 receptor ligands using ligand-based and protein-based molecular fingerprints. J. Chem. Inf. Model., 52, 3308–3324.

Strader, CD., Dixon, RA., Cheung, AH., Candelore, MR., Blake, AD., Sigal, IS., 1987, Mutations that uncouple the beta-adrenergic receptor from Gs and increase agonist affinity, J. Biol. Chem., 262, 16439-16443.

Surgand J., Rodrigo J., Kellenberger E., Rognan D., 2006, A chemogenomic analysis of the transmembrane binding cavity of human G-protein-coupled receptors. Proteins, 62, 509–538.

Suryanarayana, S. and Kobilka, BK., 1993, Amino acid substitutions at position 312 in the seventh hydrophobic segment of the β2-adrenergic receptor modify ligand-binding specificity, Mol. Pharmacol., 44, 111-114.

Tarcsay A., Paragi G., Vass M., Jójárt B., Bogár F., Keserű GM., 2013, The impact of molecular dynamics sampling on the performance of virtual screening against GPCRs. J. Chem. Inf. Model., 53, 2990–2999.

Taylor MRG., 2007, Pharmacogenetics of the human β-adrenergic receptors. Pharmacogenomics J., 7, 29–37.

Tejani-Butt, SM., Brunswick, DJ., 1986, Synthesis and beta-adrenergic receptor blocking potency of 1-(substituted amino)-3-(4-indolyloxy)propan-2-ols, J. Med. Chem., 29, 1524-1527.

Ten Brink, T., Exner, TE., 2009, Influence of protonation, tautomeric, and stereoisomeric states on protein-ligand docking results, J. Chem. Inf. Model., 49, 1535–1546.

Vroling, B., Sanders, M., Baakman, C., Borrmann, A., Verhoeven, S., Klomp, J., Oliveira, L., de Vlieg, J., Vriend, G., 2011, GPCRDB: Information system for G protein-coupled receptors, Nucleic Acids Res., 39, D309-D319.

Wacker D., Fenalti G., Brown MA., Katritch V., Abagyan R., Cherezov V., Stevens RC., 2010, Conserved binding mode of human β2 adrenergic receptor inverse agonists and antagonist revealed by X-ray crystallography. J. Am. Chem. Soc., 132, 11443–11445.

Wieland, K., Zuurmond, HM., Krasel, C., Ijzerman, AP., Lohse, MJ., 1996, Involvement of Asn-293 in stereospecific agonist recognition and in activation of the β2-adrenergic receptor, Proc. Natl. Acad. Sci. U S A., 93, 9276-9281.

Wu B., Chien EYT., Mol CD., Fenalti G., Liu W., Katritch V., Abagyan R., Brooun A., Wells P., Bi FC., Hamel DJ., Kuhn P., Handel TM., Cherezov V., Stevens RC., 2010, Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science, 330, 1066–1071.

Yakar R., Akten ED., 2014, Discovery of high affinity ligands for β2-adrenergic receptor through pharmacophore-based high-throughput virtual screening and docking. J. Mol. Graph. Model. 53, 148–160.

Yuniarti N., Ikawati Z., Istyastono EP., 2011, The importance of ARG513 as a hydrogen bond anchor to discover COX-2 inhibitors in a virtual screening campaign, Bioinformation, 6, 164–166.




DOI: http://dx.doi.org/10.14499/indonesianjpharm26iss1pp20

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