Sphingosine kinase 1 (SphK1), the enzyme that produces the bioactive sphingolipid metabolite, sphingosine-1-phosphate, is a promising new molecular target for therapeutic intervention in cancer and inflammatory diseases. In view of its importance, the main objective of this work was to find new and more potent inhibitors for this enzyme possessing different structural scaffolds than those of the known inhibitors. Our theoretical and experimental study has allowed us to identify two new structural scaffolds (three new compounds), which could be used as starting structures for the design and then the development of new inhibitors of SphK1. Our study was carried out in different steps: virtual screening, synthesis, bioassays and molecular modelling. From our results, we propose a new dihydrobenzo[b]pyrimido[5,4-f]azepine and two alkyl{3-/4-[1-hydroxy-2-(4-arylpiperazin-1-yl)ethyl]phenyl}carbamates as initial structures for the development of new inhibitors. In addition, our molecular modelling study using QTAIM calculations, allowed us to describe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analyses indicate that the cationic head of the different compounds must be refined in order to obtain an increase in the binding affinity of these ligands.

Department of Biochemistry and Molecular Biology Virginia Commonwealth University School of Medicine Richmond VA 23298 USA

Department of Chemical Drugs Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences Brno Palackeho 1 612 42 Brno Czech Republic

Department of Chemical Drugs Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences Brno Palackeho 1 612 42 Brno Czech Republic; Department of Pharmaceutical Chemistry Faculty of Pharmacy Comenius University Odbojarov 10 83232 Bratislava Slovakia

Department of Pharmaceutical Chemistry Faculty of Pharmacy Comenius University Odbojarov 10 83232 Bratislava Slovakia

Facultad de Química Bioquímica y Farmacia Universidad Nacional de San Luis Instituto Multidisciplinario de Investigaciones Biológicas Chacabuco 915 5700 San Luis Argentina

Inorganic and Organic Department University of Jaén Campus Las Lagunillas s n 23071 Jaén Spain

Institute of Analytical Chemistry of the Czech Academy of Sciences v v i Veveri 97 602 00 Brno Czech Republic

Laboratorio de Estructura Molecular y Propiedades Área de Química Física Departamento de Química Facultad de Ciencias Exactas y Naturales y Agrimensura Universidad Nacional del Nordeste Avda Libertad 5460 3400 Corrientes Argentina

Laboratorio de Síntesis Orgánica Escuela de Química Universidad Industrial de Santander Carrera 27 Calle 9 A A 678 Bucaramanga Colombia

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Blaho VA, Hla T. Regulation of mammalian physiology, development, and disease by the sphingosine 1-phosphate and lysophosphatidic acid receptors. Chem Rev. 2011;111:6299–6320. http://dx.doi.org/10.1021/cr200273u PubMed DOI PMC

Hannun YA, Obeid LM. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol. 2008;9:139–150. http://dx.doi.org/10.1038/nrm2329 PubMed DOI

Ponnusamy S, Meyers-Needham M, Senkal CE, Saddoughi SA, Sentelle D, Selvam SP, Salas A, Ogretmen B. Sphingolipids and cancer: ceramide and sphingosine-1-phosphate in the regulation of cell death and drug resistance. Future Oncol. 2010;6:1603–1624. http://dx.doi.org/10.2217/fon.10.116 PubMed DOI PMC

Spiegel S, Milstien S. The outs and the ins of sphingosine-1-phosphate in immunity. Nat Rev Immunol. 2011;11:403–415. http://dx.doi.org/10.1038/nri2974 PubMed DOI PMC

Maceyka M, Spiegel S. Sphingolipid metabolites in inflammatory disease. Nature. 2014;510:58–67. http://dx.doi.org/10.1038/nature13475 PubMed DOI PMC

Pyne S, Pyne NJ. Translational aspects of sphingosine 1-phosphate biology. Trends Mol Med. 2011;17:463–472. http://dx.doi.org/10.1016/j.molmed.2011.03.002 PubMed DOI

Pchejetski D, Bohler T, Stebbing J, Waxman J. Therapeutic potential of targeting sphingosine kinase 1 in prostate cancer. Nat Rev Urol. 2011;8:569–678. http://dx.doi.org/10.1038/nrurol.2011.117 PubMed DOI

Heffernan-Stroud LA, Obeid LM. Sphingosine kinase 1 in cancer. Adv Cancer Res. 2013;117:201–235. http://dx.doi.org/10.1016/B978-0-12-394274-6.00007-8 PubMed DOI PMC

Rodriguez YI, Campos LE, Castro MG, Aladhami A, Oskeritzian CA, Alvarez SE. Sphingosine-1 phosphate: a new modulator of immune plasticity in the tumor microenvironment. Front Oncol. 2016;6:218. http://dx.doi.org/10.3389/fonc.2016.00218 PubMed DOI PMC

Gault CR, Obeid LM. Still benched on its way to the bedside: sphingosine kinase 1 as an emerging target in cancer chemotherapy. Crit Rev Biochem Mol Biol. 2011;46:342–351. http://dx.doi.org/10.3109/10409238.2011.597737 PubMed DOI PMC

Pitman MR, Pitson SM. Inhibitors of the sphingosine kinase pathway as potential therapeutics. Curr Cancer Drug Targets. 2010;10:354–367. http://dx.doi.org/10.2174/1568210203706850096 PubMed DOI

Pyne NJ, Tonelli F, Lim KG, Long J, Edwards J, Pyne S. Targeting sphingo-sine kinase 1 in cancer. Adv Biol Regul. 2012;52:31–38. http://dx.doi.org/10.1016/j.advenzreg.2011.07.001 PubMed DOI

Pyne NJ, Tonelli F, Lim KG, Long JS, Edwards J, Pyne S. Sphingosine 1-phosphate signalling in cancer. Biochem Soc Trans. 2012;40:94–100. http://dx.doi.org/10.1042/BST20110602 PubMed DOI

Pyne NJ, Pyne S. Sphingosine 1-phosphate and cancer. Nat Rev Cancer. 2010;10:489–503. http://dx.doi.org/10.1038/nrc2875 PubMed DOI

Long JS, Edwards J, Watson C, Tovey S, Mair KM, Schiff R, Natarajan V, Pyne NJ, Pyne S. Sphingosine kinase 1 induces tolerance to human epidermal growth factor receptor 2 and prevents formation of a migratory phenotype in response to sphingosine 1-phosphate in estrogen receptor-positive breast cancer cells. Mol Cell Biol. 2010;30:3827–3841. http://dx.doi.org/10.1128/MCB.01133-09 PubMed DOI PMC

Antoon JW, Beckman BS. Sphingosine kinase: a promising cancer therapeutic target. Cancer Biol Ther. 2011;11:647–650. PubMed

Kawamori T, Kaneshiro T, Okumura M, Maalouf S, Uflacker A, Bielawski J, Hannun YA, Obeid LM. Role for sphingosine kinase 1 in colon carcinogen-esis. FASEB J Off Publ Fed Am Soc Exp Biol. 2009;23:405–414. http://dx.doi.org/10.1096/fj.08-117572 PubMed DOI PMC

Weigert A, Schiffmann S, Sekar D, Ley S, Menrad H, Werno C, Grosch S, Geisslinger G, Brune B. Sphingosine kinase 2 deficient tumor xenografts show impaired growth and fail to polarize macrophages towards an anti-inflammatory phenotype. Int J Cancer. 2009;125:2114–2121. http://dx.doi.org/10.1002/ijc.24594 PubMed DOI

Shirai K, Kaneshiro T, Wada M, Furuya H, Bielawski J, Hannun YA, Obeid LM, Ogretmen B, Kawamori T. A role of sphingosine kinase 1 in head and neck carcinogenesis. Cancer Prev Res (Phila) 2011;4:454–462. http://dx.doi.org/10.1158/1940-6207.CAPR-10-0299 PubMed DOI PMC

Bao M, Chen Z, Xu Y, Zhao Y, Zha R, Huang S, Liu L, Chen T, Li J, Tu H, He X. Sphingosine kinase 1 promotes tumour cell migration and invasion via the S1P/EDG1 axis in hepatocellular carcinoma. Liver Int. 2012;32:331–338. http://dx.doi.org/10.1111/j.1478-3231.2011.02666.x PubMed DOI

Heffernan-Stroud LA, Helke KL, Jenkins RW, De Costa AM, Hannun YA, Obeid LM. Defining a role for sphingosine kinase 1 in p53-dependent tumors. Oncogene. 2012;31:1166–1175. http://dx.doi.org/10.1038/onc.2011.302 PubMed DOI PMC

Albinet V, Bats ML, Huwiler A, Rochaix P, Chevreau C, Segui B, Levade T, Andrieu-Abadie N. Dual role of sphingosine kinase-1 in promoting the differentiation of dermal fibroblasts and the dissemination of melanoma cells. Oncogene. 2014;33:3364–3373. http://dx.doi.org/10.1038/onc.2013.303 PubMed DOI

Ponnusamy S, Selvam SP, Mehrotra S, Kawamori T, Snider AJ, Obeid LM, Shao Y, Sabbadini R, Ogretmen B. Communication between host organism and cancer cells is transduced by systemic sphingosine kinase 1/sphingosine 1-phosphate signalling to regulate tumour metastasis. EMBO Mol Med. 2012;4:761–775. http://dx.doi.org/10.1002/emmm.201200244 PubMed DOI PMC

Kohno M, Momoi M, Oo ML, Paik JH, Lee YM, Venkataraman K, Ai Y, Ristimaki AP, Fyrst H, Sano H, Rosenberg D, Saba JD, Proia RL, Hla T. Intracellular role for sphingosine kinase 1 in intestinal adenoma cell proliferation. Mol Cell Biol. 2006;26:7211–7223. http://dx.doi.org/10.1128/MCB.02341-05 PubMed DOI PMC

Truman JP, Garcia-Barros M, Obeid LM, Hannun YA. Evolving concepts in cancer therapy through targeting sphingolipid metabolism. Biochim Biophys Acta. 2014;1841:1174–1188. http://dx.doi.org/10.1016/j.bbalip.2013.12.013 PubMed DOI PMC

Orr Gandy KA, Obeid LM. Targeting the sphingosine kinase/sphingosine 1-phosphate pathway in disease: review of sphingosine kinase inhibitors. Bio-chim Biophys Acta. 2013;1831:157–166. http://dx.doi.org/10.1016/j.bbalip.2012.07.002 PubMed DOI PMC

Takabe K, Paugh SW, Milstien S, Spiegel S. “Inside-out” signaling of sphingosine-1-phosphate: therapeutic targets. Pharmacol Rev. 2008;60:181–195. http://dx.doi.org/10.1124/pr.107.07113 PubMed DOI PMC

Wang Z, Min X, Xiao SH, Johnstone S, Romanow W, Meininger D, Xu H, Liu J, Dai J, An S, Thibault S, Walker N. Molecular basis of sphingosine kinase 1 substrate recognition and catalysis. Structure. 2013;21:798–809. http://dx.doi.org/10.1016/j.str.2013.02.025 PubMed DOI

Gustin DJ, Li Y, Brown ML, Min X, Schmitt MJ, Wanska M, Wang X, Connors R, Johnstone S, Cardozo M, Cheng AC, Jeffries S, Franks B, Li S, Shen S, Wong M, Wesche H, Xu G, Carlson TJ, Plant M, Morgenstern K, Rex K, Schmitt J, Coxon A, Walker N, Kayser F, Wang Z. Structure guided design of a series of sphingosine kinase (SphK) inhibitors. Bioorg Med Chem Lett. 2013;23:4608–4616. http://dx.doi.org/10.1016/j.bmcl.2013.06.030 PubMed DOI

Wang J, Knapp S, Pyne NJ, Pyne S, Elkins JM. Crystal structure of sphingosine kinase 1 with PF-543. ACS Med Chem Lett. 2014;5:1329–1333. http://dx.doi.org/10.1021/ml5004074 PubMed DOI PMC

Paugh SW, Paugh BS, Rahmani M, Kapitonov D, Almenara JA, Kordula T, Milstien S, Adams JK, Zipkin RE, Grant S, Spiegel S. A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia. Blood. 2008;112:1382–1391. http://dx.doi.org/10.1182/blood-2008-02-138958 PubMed DOI PMC

French KJ, Schrecengost RS, Lee BD, Zhuang Y, Smith SN, Eberly JL, Yun JK, Smith CD. Discovery and evaluation of inhibitors of human sphingosine kinase. Cancer Res. 2003;63:5962–5969. PubMed

Mathews TP, Kennedy AJ, Kharel Y, Kennedy PC, Nicoara O, Sunkara M, Morris AJ, Wamhoff BR, Lynch KR, MacDonald TL. Discovery, biological evaluation, and structure-activity relationship of amidine based sphingosine kinase inhibitors. J Med Chem. 2010;53:2766–2778. http://dx.doi.org/10.1021/jm901860h PubMed DOI PMC

Xiang Y, Hirth B, Kane JLJ, Liao J, Noson KD, Yee C, Asmussen G, Fitzgerald M, Klaus C, Booker M. Discovery of novel sphingosine kinase-1 inhibitors Part 2. Bioorg Med Chem Lett. 2010;20:4550–4554. http://dx.doi.org/10.1016/j.bmcl.2010.06.019 PubMed DOI

Baek DJ, MacRitchie N, Pyne NJ, Pyne S, Bittman R. Synthesis of selective inhibitors of sphingosine kinase 1. Chem Commun. 2013;49:2136–2138. http://dx.doi.org/10.1039/C3CC00181D PubMed DOI PMC

Schnute ME, McReynolds MD, Kasten T, Yates M, Jerome G, Rains JW, Hall T, Chrencik J, Kraus M, Cronin CN, Saabye M, Highkin MK, Broadus R, Ogawa S, Cukyne K, Zawadzke LE, Peterkin V, Iyanar K, Scholten JA, Wendling J, Fujiwara H, Nemirovskiy O, Wittwer AJ, Nagiec MM. Modulation of cellular S1P levels with a novel, potent and specific inhibitor of sphingosine kinase-1. Biochem J. 2012;444:79–88. http://dx.doi.org/10.1042/BJ20111929 PubMed DOI

Patwardhan NN, Morris EA, Kharel Y, Raje MR, Gao M, Tomsig JL, Lynch KR, Santos WL. Structure–Activity relationship studies and in vivo activity of guanidine-based sphingosine kinase inhibitors: discovery of SphK1- and SphK2-selective inhibitors. J Med Chem. 2015;58:1879–1899. http://dx.doi.org/10.1021/jm501760d PubMed DOI PMC

Pitman MR, Costabile M, Pitson SM. Recent advances in the development of sphingosine kinase inhibitors. Cell Signal. 2016;28:1349–1363. http://dx.doi.org/10.1016/j.cellsig.2016.06.007 PubMed DOI

Gao Y, Gao F, Chen K, Tian M, Zhao D. Sphingosine kinase 1 as an anticancer therapeutic target. Drug Des devel Ther. 2015;9:3239–3245. http://dx.doi.org/10.2147/DDDT.S83288 PubMed DOI PMC

Newton J, Lima S, Maceyka M, Spiegel S. Revisiting the sphingolipid rheostat: evolving concepts in cancer therapy. Exp Cell Res. 2015;333:195–200. http://dx.doi.org/10.1016/j.yexcr.2015.02.025 PubMed DOI PMC

Santos WL, Lynch KR. Drugging sphingosine kinases. ACS Chem Biol. 2015;10:225–233. http://dx.doi.org/10.1021/cb5008426 PubMed DOI PMC

Pellecchia M. Fragment-based drug discovery takes a virtual turn. Nat Chem Biol. 2009;5:274–275. http://dx.doi.org/10.1038/nchembio0509-274 PubMed DOI

Zheng W, Johnson SR, Baskin I, Bajorath J, Horvath D, Laggner C, Langer T, Schneider G, Filimonov D, Poroikov V, Tetko I, Van De Waterbeemd H, Oprea T, Radchenko E, Palyulin V, Zefirov N, Peltason L, Wolber G, Schuster D, Kirchmair J, Proschak E, Tanrikulu Y, Varnek A, Tropsha A. Chemoinformatics approaches to virtual screening. R Soc Chem. 2008 http://dx.doi.org/10.1039/9781847558879 DOI

Triballeau N, Bertrand HO, Acher F. Pharmacophores and Pharmacophore Searches. Wiley-VCH Verlag GmbH & Co KGaA; 2006. Are you sure you have a good model? pp. 325–364.http://dx.doi.org/10.1002/3527609164.ch15 DOI

Gaulton A, Bellis LJ, Bento AP, Chambers J, Davies M, Hersey A, Light Y, McGlinchey S, Michalovich D, Al-Lazikani B, Overington JP. ChEMBL: a large-scale bioactivity database for drug discovery. Nucleic Acids Res. 2012;40:D1100–D1107. http://dx.doi.org/10.1093/nar/gkr777 PubMed DOI PMC

Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010;31:455–461. http://dx.doi.org/10.1002/jcc.21334 PubMed DOI PMC

Sutherland JJ, Nandigam RK, Erickson JA, Vieth M. Lessons in molecular recognition. 2. Assessing and improving cross-docking accuracy. J Chem Inf Model. 2007;47:2293–2302. http://dx.doi.org/10.1021/ci700253h PubMed DOI

O'Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open Babel: an open chemical toolbox. J Cheminform. 2011;3:33. http://dx.doi.org/10.1186/1758-2946-3-33 PubMed DOI PMC

Stanzel L, Malik I, Mokry P. Preliminary in vitro investigation of antioxidant potential of ultra short acting arylcarbamoyloxy-aminopropanols containing N-phenylpiperazine moiety. Dhaka Univ J Pharm Sci. 2016;15:235–239. http://dx.doi.org/10.3329/dujps.v15i2.30943 DOI

Malík I, Janoscova M, Mokrý P, Csollei J, Andriamainty F. Basic physicochemical characterization of new potential ultrashort acting b 1-adre-noceptor blockers. Acta Fac Pharm Univ Comen. 2009;56:119–127.

Malik I, Bukovsky M, Mokrý P, Csollei J. Antimicrobial profile investigation of potential ultrashort acting beta-adrenoceptor blocking compounds containing N-phenylpiperazine moiety. Glob J Med Res. 2013;13:1–4.

Acosta-Quintero LM, Jurado J, Nogueras M, Palma A, Cobo J. Synthesis of pyrimidine-fused benzazepines from 5-Allyl-4,6-dichloropyrimidines. Eur J Org Chem. 2015;2015:5360–5369. http://dx.doi.org/10.1002/ejoc.201500632 DOI

Tengler J, Kapustíkova I, Pesko M, Govender R, Keltosova S, Mokrý P, Kollar P, OMahony J, Coffey A, Kralova K. Jampílek, Synthesis and Biological evaluation of 2-Hydroxy-3-[(2-aryloxyethyl)amino]propyl 4-[(alkox-ycarbonyl)amino]benzoates. Sci World J. 2013;2013:274570. http://dx.doi.org/10.1155/2013/274570 PubMed DOI PMC

Tengler J, Kapustíkova I, Stropnický O, Mokrý P, Oravec M, Csollei J, Jampílek J. Synthesis of new (arylcarbonyloxy)aminopropanol derivatives and the determination of their physico-chemical properties. Cent Eur J Chem. 2013;11:1757–1767. http://dx.doi.org/10.2478/s11532-013-0302-8 DOI

Marvanova P, Padrtova T, Pekarek T, Brus J, Czernek J, Mokry P, Humpa O, Oravec M, Jampilek J. Synthesis and characterization of new 3-(4-Arylpiperazin-1-yl)-2-hydroxypropyl 4-propoxybenzoates and their hydrochloride salts. Molecules. 2016;21 http://dx.doi.org/10.3390/molecules21060707 PubMed DOI PMC

Gaster LM, Jennings AJ, Joiner GF, King FD, Mulholland KR, Rahman SK, Starr S, Wyman PA, Wardle KA. (1-Butyl-4-piperidinyl)methyl 8-amino-7-chloro-1,4-benzodioxane-5-carboxylate hydrochloride: a highly potent and selective 5-HT4 receptor antagonist derived from metoclopramide. J Med Chem. 1993;36:4121–4123. http://dx.doi.org/10.1021/jm00077a018 PubMed DOI

Lalut J, Tournier BB, Cailly T, Lecoutey C, Corvaisier S, Davis A, Ballandonne C, Since M, Millet P, Fabis F, Dallemagne P, Rochais C. Synthesis and evaluation of novel serotonin 4 receptor radiotracers for singlephoton emission computed tomography. Eur J Med Chem. 2016;116:90–101. http://dx.doi.org/10.1016/j.ejmech.2016.03.059 PubMed DOI

Kettmann V, Csollei J, Račanská E, Švec P. Synthesis and structure-activity relationships of new β-adrenoreceptor antagonists. Evidence for the electrostatic requirements for β-adrenoreceptor antagonists. Eur J Med Chem. 1991;26:843–851. http://dx.doi.org/10.1016/0223-5234(91)90127-9 DOI

Koelsch ST, Rolfson CF. Synthesis of certain 3,4-disubstituted piperidines. J Amer Chem Soc. 1950;72:1871–1873.

Ammazzalorso A, Amoroso R, Bettoni G, Fantacuzzi M, De Filippis B, Giampietro L, Maccallini C, Paludi D, Tricca ML. Synthesis and antibacterial evaluation of oxazolidin-2-ones structurally related to linezolid. Farmaco. 2004;59:685–690. http://dx.doi.org/10.1016/j.farmac.2004.05.002 PubMed DOI

Dewar DR, Kapur GH, Mottram H. Some potential α-adrenoreceptor blocking 1,4-benzodioxanes and 2,6-dimethoxyphenoxyethylamines. Eur J Med Chem. 1983;18:286–290.

Marvanova P, Padrtova T, Odehnalova K, Hosik O, Oravec M, Mokry P. Synthesis and determination of physicochemical properties of new 3-(4-Arylpiperazin-1-yl)-2-hydroxypropyl 4-alkoxyethoxybenzoates. Molecules. 2016;21 http://dx.doi.org/10.3390/molecules21121682 PubMed DOI PMC

Lima S, Milstien S, Spiegel S. A real-time high-throughput fluorescence assay for sphingosine kinases. J Lipid Res. 2014;55:1525–1530. http://dx.doi.org/10.1194/jlr.D048132 PubMed DOI PMC

Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem. 2009;30:2785–2791. http://dx.doi.org/10.1002/jcc.21256 PubMed DOI PMC

Case DA, Darden TA, Cheatham TE, Simmerling CL, Wang J, Duke RE, Luo R, Walker RC, Zhang W, Merz KM, Roberts B, Hayik S, Roitberg A, Seabra G, Swails J, Goetz AW, Kolossvary I, Wong KF, Paesani F, Vanicek J, Wolf RM, Liu J, Wu X, Brozell SR, Steinbrecher T, Gohlke H, Cai Q, Ye X, Wang J, Hsieh MJ, Cui G, Roe DR, Mathews DH, Seetin MG, Salomon-Ferrer R, Sagui C, Babin V, Luchko T, Gusarov S, Kovalenko A, Kollman PA. AMBER 12 OR. University of California; San Francisco: 2012. citeulike-article-id:10779586.

Andújar SA, Tosso RD, Suvire FD, Angelina E, Peruchena N, Cabedo N, Cortés D, Enriz RD. Searching the “biologically relevant” conformation of dopamine: a computational approach. J Chem Inf Model. 2012;52:99–112. http://dx.doi.org/10.1021/ci2004225 PubMed DOI

Tosso RD, Andújar SA, Gutierrez L, Angelina E, Rodríguez R, Nogueras M, Baldoni H, Suvire FD, Cobo J, Enriz RD. Molecular modeling study of dihydrofolate reductase inhibitors. Molecular dynamics simulations, quantum mechanical calculations, and experimental corroboration. J Chem Inf Model. 2013;53:2018–2032. http://dx.doi.org/10.1021/ci400178h PubMed DOI

Parraga J, Cabedo N, Andújar S, Piqueras L, Moreno L, Galan A, Angelina E, Enriz RD, Ivorra MD, Sanz MJ, Cortes D. 2,3,9- and 2,3,11-trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands. Eur J Med Chem. 2013;68:150–166. http://dx.doi.org/10.1016/j.ejmech.2013.07.036 PubMed DOI

Angelina EL, Andújar SA, Tosso RD, Enriz RD, Peruchena NM. Non-covalent interactions in receptor–ligand complexes. A study based on the electron charge density. J Phys Org Chem. 2014;27:128–134. http://dx.doi.org/10.1002/poc.3250 DOI

Parraga J, Andújar SA, Rojas S, Gutié LJ, El Aouad N, Sanz MJ, Enriz RD, Cabedo N, Cortes D. Dopaminergic isoquinolines with hexahydrocyclopenta[ij]-isoquinolines as D2-like selective ligands. Eur J Med Chem. 2016;122:27–42. http://dx.doi.org/10.1016/j.ejmech.2016.06.009 PubMed DOI

Adams DR, Pyne S, Pyne NJ. Sphingosine kinases: emerging structure-function insights. Trends biochem Sci. 2016;41:395–409. http://dx.doi.org/10.1016/j.tibs.2016.02.007 PubMed DOI

Pulkoski-Gross MJ, Donaldson JC, Obeid LM. Sphingosine-1-phosphate metabolism: a structural perspective. Crit Rev Biochem Mol Biol. 2015;50:298–313. http://dx.doi.org/10.3109/10409238.2015.1039115 PubMed DOI PMC

Parthasarathi R, Subramanian V, Sathyamurthy N. Hydrogen bonding without Borders: an atoms-in-molecules perspective. J Phys Chem A. 2006;110:3349–3351. http://dx.doi.org/10.1021/jp060571z PubMed DOI

Witek S, Bielawski J, Bielawska A. Synthesis of N-(Formylphenyl)- and N-(Acetophenyl) derivatives of urea and carbamic acid. J Für Prakt Chem. 1979;321:804–812. http://dx.doi.org/10.1002/prac.19793210512 DOI

Sing T, Sander O, Beerenwinkel N, Lengauer T. ROCR: visualizing classifier performance in R. Bioinformatics. 2005;21:3940–3941. http://dx.doi.org/10.1093/bioinformatics/bti623 PubMed DOI

R Development Core Team. R: a language and environment for statistical computing. 3-900051-07-0R Found Stat Comput. 2011 http://www.r-project.org/

John RW, Eaton W. David Bateman, Søren Hauberg, GNU Octave version 3.8.1 manual: a high-level interactive language for numerical computations. Creat Indep Publ Platf. 2014 Item 26.4 http://www.gnu.org/software/octave/doc/interpreter/

Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem. 1998;19:1639–1662. http://dx.doi.org/10.1002/(SICI)1096-987X(19981115)19 , 14<1639∷AID-JCC10>3.0.CO;2-B. DOI

Ewing TJA, Kuntz ID. Critical evaluation of search algorithms for automated molecular docking and database screening. J Comput Chem. 1997;18:1175–1189. http://dx.doi.org/10.1002/(SICI)1096-987X(19970715)18 , 9<1175∷AID-JCC6>3.0.CO;2-O. DOI

Mark P, Nilsson L. Structure and dynamics of the TIP3P, SPC, and SPC/e water models at 298 K. J Phys Chem A. 2001;105:9954–9960. http://dx.doi.org/10.1021/jp003020w DOI

Darden T, York D, Pedersen L. Particle mesh Ewald: an N,log(N) method for Ewald sums in large systems. J Chem Phys. 1993;98

Bader RFW. Atoms in molecules. Acc Chem Res. 1985;18:9–15. http://dx.doi.org/10.1021/ar00109a003 DOI

Lu T, Chen F. Multiwfn: a multifunctional wavefunction analyzer. J Comput Chem. 2012;33:580–592. http://dx.doi.org/10.1002/jcc.22885 PubMed DOI

Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Barone GW, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Li MW, Li X, Hratchian HP, Izmaylov AF, JA, JEP, FO, MB, JJH, EB, KNK, VNS, RK, JN, KR, AR, JCB, SSI, JT, MC . Gaussian 09. Vol. 2009 Gaussian Inc; Wallingford CT: 2009.

Barrera Guisasola EE, Gutierrez LJ, Andujar SA, Angelina E, Rodriguez AM, Enriz RD. Pentameric models as alternative molecular targets for the design of new antiaggregant agents. Curr Protein Pept Sci. 2016;17:156–168. PubMed

Luchi AM, Angelina EL, Andujar SA, Enriz RD, Peruchena NM. Halogen bonding in biological context: a computational study of D2 dopamine receptor. J Phys Org Chem. 2016;29:645–655. http://dx.doi.org/10.1002/poc.3586 DOI

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