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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Determination of Hybrid TSPO Ligands with Minimal Impact of SNP (rs6971) through Molecular Docking and MD Simulation Study

Author(s): Anupriya Adhikari*, Anwesh Pandey, Devesh Kumar and Anjani K. Tiwari*

Volume 19, Issue 6, 2022

Published on: 13 April, 2021

Page: [549 - 563] Pages: 15

DOI: 10.2174/1570180818666210413130326

Price: $65

Abstract

Background: In an endeavor to ascertain high-affinity TSPO ligands with minimal single nucleotide polymorphism (SNP), six hybrid molecules have been identified as new leads for future inflammation PET imaging.

Objective: Genesis for chemical design was encouraged from structural families of well-known ligands FEBMP and PBR28/ DAA1106 that have demonstrated remarkable TSPO binding characteristics.

Methods: All proposed hybrid ligands 1-6 are subjected to molecular docking and simulation studies with wild and mutant protein to study their interactions, binding, consistency of active conformations and are correlated with well-established TSPO ligands.

Results: Each hybrid ligand demonstrate better docking score > -11.00 kcal/mol with TSPO with respect to gold standard PK11195, i.e., -11.00 kcal/mol for 4UC3 and -12.94 kcal/mol for 4UC1. On comparison with FEBMP and GE-180 ({-12.57, -7.24 kcal/mol} for 4UC3 and {-14.10, -11.32 kcal/mol} for 4UC1), ligand 3 demonstrates maximum docking energy (> -15.50 kcal/mol) with minimum SNP (0.26 kcal/mol).

Discussion: Presence of strong hydrogen bond Arg148-3.27Å (4UC1) and Trp50-2.43Å, Asp28- 2.57Å (4UC3) apart from short-range interactions, including π–π interactions with the aromatic residues, such as (Trp39, Phe46, Trp135) and (Trp39, Trp108), attributes towards its strong binding.

Conclusion: Utilizing the results of binding energy, we concluded stable complex formation of these hybrid ligands that could bind to TSPO with the least effect of SNP with similar interactions to known ligands. Overall, ligand 3 stands out as the best ligand having insignificant deviations per residue of protein that can be further explored and assessed in detail for future inflammation PET application after subsequent detailed biological evaluation.

Keywords: TSPO, PET, docking, molecular simulation, rs6971, hybrid ligands.

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[1]
Braestrup, C.; Squires, R.F. Specific benzodiazepine receptors in rat brain characterized by high-affinity (3H)diazepam binding. Proc. Natl. Acad. Sci. USA, 1977, 74(9), 3805-3809.
[http://dx.doi.org/10.1073/pnas.74.9.3805] [PMID: 20632]
[2]
Casellas, P.; Galiegue, S.; Basile, A.S. Peripheral benzodiazepine receptors and mitochondrial function. Neurochem. Int., 2002, 40(6), 475-486.
[http://dx.doi.org/10.1016/S0197-0186(01)00118-8] [PMID: 11850104]
[3]
Papadopoulos, V.; Lecanu, L.; Brown, R.C.; Han, Z.; Yao, Z.X. Peripheral-type benzodiazepine receptor in neurosteroid biosynthesis, neuropathology and neurological disorders. Neuroscience, 2006, 138(3), 749-756.
[http://dx.doi.org/10.1016/j.neuroscience.2005.05.063] [PMID: 16338086]
[4]
Rone, M.B.; Fan, J.; Papadopoulos, V. Cholesterol transport in steroid biosynthesis: role of protein-protein interactions and implications in disease states. Biochim. Biophys. Acta, 2009, 1791(7), 646-658.
[http://dx.doi.org/10.1016/j.bbalip.2009.03.001] [PMID: 19286473]
[5]
Veenman, L.; Gavish, M. Peripheral benzodiazepine receptors: Their implication in brain disease. Drug Dev. Res., 2000, 50, 355-370.
[http://dx.doi.org/10.1002/1098-2299(200007/08)50:3/4<355:AID-DDR18>3.0.CO;2-W]
[6]
Li, F.; Liu, J.; Liu, N.; Kuhn, L.A.; Garavito, R.M.; Ferguson-Miller, S. Translocator protein 18 kDa (TSPO): An old protein with new functions? Biochemistry, 2016, 55(20), 2821-2831.
[http://dx.doi.org/10.1021/acs.biochem.6b00142] [PMID: 27074410]
[7]
Banati, R.B. Visualising microglial activation in vivo. Glia, 2002, 40(2), 206-217.
[http://dx.doi.org/10.1002/glia.10144] [PMID: 12379908]
[8]
Narayan, N.; Mandhair, H.; Smyth, E.; Dakin, S.G.; Kiriakidis, S.; Wells, L.; Owen, D.; Sabokbar, A.; Taylor, P. The macrophage marker translocator protein (TSPO) is down-regulated on pro-inflammatory ‘M1’ human macrophages. PLoS One, 2017, 12(10), e0185767.
[http://dx.doi.org/10.1371/journal.pone.0185767] [PMID: 28968465]
[9]
Guilarte, T.R. TSPO in diverse CNS pathologies and psychiatric disease: A critical review and a way forward. Pharmacol. Ther., 2019, 194, 44-58.
[http://dx.doi.org/10.1016/j.pharmthera.2018.09.003] [PMID: 30189290]
[10]
Kreisl, W.C.; Fujita, M.; Fujimura, Y.; Kimura, N.; Jenko, K.J.; Kannan, P.; Hong, J.; Morse, C.L.; Zoghbi, S.S.; Gladding, R.L.; Jacobson, S.; Oh, U.; Pike, V.W.; Innis, R.B. Comparison of [(11)C]-(R)-PK 11195 and [(11)C]PBR28, two radioligands for translocator protein (18 kDa) in human and monkey: Implications for positron emission tomographic imaging of this inflammation biomarker. Neuroimage, 2010, 49(4), 2924-2932.
[http://dx.doi.org/10.1016/j.neuroimage.2009.11.056] [PMID: 19948230]
[11]
Chauveau, F.; Boutin, H.; Van Camp, N.; Dollé, F.; Tavitian, B. Nuclear imaging of neuroinflammation: a comprehensive review of [11C]PK11195 challengers. Eur. J. Nucl. Med. Mol. Imaging, 2008, 35(12), 2304-2319.
[http://dx.doi.org/10.1007/s00259-008-0908-9] [PMID: 18828015]
[12]
Owen, D.R.; Yeo, A.J.; Gunn, R.N.; Song, K.; Wadsworth, G.; Lewis, A.; Rhodes, C.; Pulford, D.J.; Bennacef, I.; Parker, C.A.; StJean, P.L.; Cardon, L.R.; Mooser, V.E.; Matthews, P.M.; Rabiner, E.A.; Rubio, J.P. An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J. Cereb. Blood Flow Metab., 2012, 32(1), 1-5.
[http://dx.doi.org/10.1038/jcbfm.2011.147] [PMID: 22008728]
[13]
Owen, D.R.; Lewis, A.J.; Reynolds, R.; Rupprecht, R.; Eser, D.; Wilkins, M.R.; Bennacef, I.; Nutt, D.J.; Parker, C.A. Variation in binding affinity of the novel anxiolytic XBD173 for the 18 kDa translocator protein in human brain. Synapse, 2011, 65(3), 257-259.
[http://dx.doi.org/10.1002/syn.20884] [PMID: 21132812]
[14]
Owen, D.R.; Gunn, R.N.; Rabiner, E.A.; Bennacef, I.; Fujita, M.; Kreisl, W.C.; Innis, R.B.; Pike, V.W.; Reynolds, R.; Matthews, P.M.; Parker, C.A. Mixed-affinity binding in humans with 18-kDa translocator protein ligands. J. Nucl. Med., 2011, 52(1), 24-32.
[http://dx.doi.org/10.2967/jnumed.110.079459] [PMID: 21149489]
[15]
Owen, D.R.; Fan, J.; Campioli, E.; Venugopal, S.; Midzak, A.; Daly, E.; Harlay, A.; Issop, L.; Libri, V.; Kalogiannopoulou, D.; Oliver, E.; Gallego-Colon, E.; Colasanti, A.; Huson, L.; Rabiner, E.A.; Suppiah, P.; Essagian, C.; Matthews, P.M.; Papadopoulos, V. TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis. Biochem. J., 2017, 474(23), 3985-3999.
[http://dx.doi.org/10.1042/BCJ20170648] [PMID: 29074640]
[16]
Gudasheva, T.A.; Deeva, O.A.; Mokrov, G.V.; Dyabina, A.S.; Yarkova, M.A.; Seredenin, S.B. Design, Synthesis and Anxiolytic Activity Evaluation of N-Acyltryptophanyl- Containing Dipeptides, Potential TSPO Ligands. Med. Chem., 2019, 15(4), 383-399.
[http://dx.doi.org/10.2174/1573406415666181119164846] [PMID: 30457052]
[17]
Nag, S.; Krasikova, R.; Airaksinen, A.J.; Arakawa, R.; Petukhovd, M.; Gulyas, B. Synthesis and biological evaluation of [18F]fluorovinpocetine, a potential PET radioligand for TSPO imaging. Bioorg. Med. Chem. Lett., 2019, 29(16), 2270-2274.
[http://dx.doi.org/10.1016/j.bmcl.2019.06.037] [PMID: 31257082]
[18]
Srivastava, P.; Kakkar, D.; Kumar, P.; Tiwari, A.K. Modified benzoxazolone (ABO-AA) based single photon emission computed tomography (SPECT) probes for 18 kDa translocator protein. Drug Dev. Res., 2019, 80(6), 741-749.
[http://dx.doi.org/10.1002/ddr.21547] [PMID: 31184784]
[19]
Kumari, N.; Chadha, N.; Srivastava, P.; Mishra, L.C.; Bhagat, S.; Mishra, A.K.; Tiwari, A.K. Modified benzoxazolone derivative as 18-kDa TSPO ligand. Chem. Biol. Drug Des., 2017, 90(4), 511-519.
[http://dx.doi.org/10.1111/cbdd.12971] [PMID: 28267890]
[20]
Cheng, H.W.A.; Sokias, R.; Werry, E.L.; Ittner, L.M.; Reekie, T.A.; Du, J.; Gao, Q.; Hibbs, D.E.; Kassiou, M. First Nondiscriminating Translocator Protein Ligands Produced from a Carbazole Scaffold. J. Med. Chem., 2019, 62(17), 8235-8248.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00980] [PMID: 31419132]
[21]
Sokias, R.; Werry, E.L.; Chua, S.W.; Reekie, T.A.; Munoz, L.; Wong, E.C.N.; Ittner, L.M.; Kassiou, M. Determination and reduction of translocator protein (TSPO) ligand rs6971 discrimination. MedChemComm, 2016, 8(1), 202-210.
[http://dx.doi.org/10.1039/C6MD00523C] [PMID: 30108706]
[22]
Tiwari, A.K.; Ji, B.; Yui, J.; Fujinaga, M.; Yamasaki, T.; Xie, L.; Luo, R.; Shimoda, Y.; Kumata, K.; Zhang, Y.; Hatori, A.; Maeda, J.; Higuchi, M.; Wang, F.; Zhang, M.R. [18F]FEBMP: Positron Emission Tomography Imaging of TSPO in a Model of Neuroinflammation in Rats, and in vitro Autoradiograms of the Human Brain. Theranostics, 2015, 5(9), 961-969.
[http://dx.doi.org/10.7150/thno.12027] [PMID: 26155312]
[23]
Fukaya, T.; Kodo, T.; Ishiyama, T.; Kakuyama, H.; Nishikawa, H.; Baba, S.; Masumoto, S. Design, synthesis and structure-activity relationships of novel benzoxazolone derivatives as 18 kDa translocator protein (TSPO) ligands. Bioorg. Med. Chem., 2012, 20(18), 5568-5582.
[http://dx.doi.org/10.1016/j.bmc.2012.07.023] [PMID: 22884355]
[24]
Dolatkhah, Z.; Javanshir, S.; Sadr, A.S.; Hosseini, J.; Sardari, S. synthesis, molecular docking, molecular dynamics studies, and biological evaluation of 4H-Chromone-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives as potential antileukemic agents. J. Chem. Inf. Model., 2017, 57(6), 1246-1257.
[http://dx.doi.org/10.1021/acs.jcim.6b00138] [PMID: 28524659]
[25]
Bhatia, S.; Kumar, V.; Singh, S.; Singh, J. Synthesis, biological activities and docking studies of piperazine incorporated 1, 3, 4-oxadiazole derivatives. J. Mol. Struct., 2019, 1191, 197-205.
[http://dx.doi.org/10.1016/j.molstruc.2019.04.106]
[26]
Abraham, M.J.; Murtola, T.; Schulz, R.; Pall, S.; Smith, J.C.; Hess, B.; Lindahl, E. SoftwareX, 2015, 1–2, 19-25.
[http://dx.doi.org/10.1016/j.softx.2015.06.001]
[27]
Sapay, N.; Tieleman, D.P. Combination of the CHARMM27 force field with united-atom lipid force fields. J. Comput. Chem., 2011, 32(7), 1400-1410.
[http://dx.doi.org/10.1002/jcc.21726] [PMID: 21425293]
[28]
Zoete, V.; Cuendet, M.A.; Grosdidier, A.; Michielin, O. SwissParam: a fast force field generation tool for small organic molecules. J. Comput. Chem., 2011, 32(11), 2359-2368.
[http://dx.doi.org/10.1002/jcc.21816] [PMID: 21541964]
[29]
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]
[30]
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, 10089-10092.
[http://dx.doi.org/10.1063/1.464397]
[31]
Ryckaert, J.P.; Ciccotti, G.; Berendsen, H.J. Numerical integration of the Cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J. Comput. Phys., 1977, 23, 327-341.
[http://dx.doi.org/10.1016/0021-9991(77)90098-5]
[32]
Hess, B.; Bekker, H.; Berendsen, H.J.C.; Fraaije, J.G.E.M. LINCS: A linear constraint solver for molecular simulations. J. Comput. Chem., 1997, 18, 1463-1472.
[http://dx.doi.org/10.1002/(SICI)1096-987X(199709)18:12<1463:AID-JCC4>3.0.CO;2-H]
[33]
Turner, P.J. XMGRACE, Version 5.1. 19; Center for coastal and land-margin research, oregon graduate institute of science and technology, beaverton 2005.
[34]
Srivastava, P.; Kaul, A.; Ojha, H.; Kumar, P.; Tiwari, A.K. Design, synthesis and biological evaluation of methyl-2-(2-(5-bromo benzoxazolone)acetamido)-3-(1H-indol-3-yl)propanoate: TSPO ligand for SPECT. RSC Advances, 2016, 6, 114491-114499.
[http://dx.doi.org/10.1039/C6RA19514H]
[35]
Shah, F.; Hume, S.P.; Pike, V.W.; Ashworth, S.; McDermott, J. Synthesis of the enantiomers of [N-methyl-11C]PK 11195 and comparison of their behaviours as radioligands for PK binding sites in rats. Nucl. Med. Biol., 1994, 21(4), 573-581.
[http://dx.doi.org/10.1016/0969-8051(94)90022-1] [PMID: 9234314]
[36]
Zhang, M.R.; Kida, T.; Noguchi, J.; Furutsuka, K.; Maeda, J.; Suhara, T.; Suzuki, K. [(11)C]DAA1106: radiosynthesis and in vivo binding to peripheral benzodiazepine receptors in mouse brain. Nucl. Med. Biol., 2003, 30(5), 513-519.
[http://dx.doi.org/10.1016/S0969-8051(03)00016-7] [PMID: 12831989]
[37]
Kumata, K.; Zhang, Y.; Fujinaga, M.; Ohkubo, T.; Mori, W.; Yamasaki, T.; Hanyu, M.; Xie, L.; Hatori, A.; Zhang, M.R. [18F]DAA1106: Automated radiosynthesis using spirocyclic iodonium ylide and preclinical evaluation for positron emission tomography imaging of translocator protein (18 kDa). Bioorg. Med. Chem., 2018, 26(17), 4817-4822.
[http://dx.doi.org/10.1016/j.bmc.2018.08.017] [PMID: 30166255]
[38]
Zhang, M.R.; Ogawa, M.; Maeda, J.; Ito, T.; Noguchi, J.; Kumata, K.; Okauchi, T.; Suhara, T.; Suzuki, K. [2-11C]isopropyl-, [1-11C]ethyl-, and [11C]methyl-labeled phenoxyphenyl acetamide derivatives as positron emission tomography ligands for the peripheral benzodiazepine receptor: radiosynthesis, uptake, and in vivo binding in brain. J. Med. Chem., 2006, 49(9), 2735-2742.
[http://dx.doi.org/10.1021/jm060006k] [PMID: 16640334]
[39]
Graeber, E.; Korkhov, V.M. Characterisation of the ligand binding sites in the translocator protein TSPO using the chimeric bacterial-mammalian constructs. Protein Expr. Purif., 2019, 164, 105456.
[http://dx.doi.org/10.1016/j.pep.2019.105456] [PMID: 31326501]
[40]
Hieu Tran, V.; Park, H.; Park, J.; Kwon, Y.D.; Kang, S.; Ho Jung, J.; Chang, K.A.; Chul Lee, B.; Lee, S.Y.; Kang, S.; Kim, H.K. Synthesis and evaluation of novel potent TSPO PET ligands with 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamide. Bioorg. Med. Chem., 2019, 27(18), 4069-4080.
[http://dx.doi.org/10.1016/j.bmc.2019.07.036] [PMID: 31353076]
[41]
Tiwari, A.K.; Fujinaga, M.; Yui, J.; Yamasaki, T.; Xie, L.; Kumata, K.; Mishra, A.K.; Shimoda, Y.; Hatori, A.; Ji, B.; Ogawa, M.; Kawamura, K.; Wang, F.; Zhang, M.R. Synthesis and evaluation of new (18)F-labelled acetamidobenzoxazolone-based radioligands for imaging of the translocator protein (18 kDa, TSPO) in the brain. Org. Biomol. Chem., 2014, 12(47), 9621-9630.
[http://dx.doi.org/10.1039/C4OB01933D] [PMID: 25339090]
[42]
Deeva, O.A.; Pantileev, A.S.; Rybina, I.V.; Yarkova, M.A.; Gudasheva, T.A.; Seredenin, S.B. A novel dipeptide ligand of TSPO. Dokl. Biochem. Biophys., 2019, 484(1), 17-20.
[http://dx.doi.org/10.1134/S1607672919010046] [PMID: 31012004]
[43]
Chadha, N.; Tiwari, A.K.; Kumar, V.; Lal, S.; Milton, M.D.; Mishra, A.K. Oxime-dipeptides as anticholinesterase, reactivator of phosphonylated-serine of AChE catalytic triad: probing the mechanistic insight by MM-GBSA, dynamics simulations and DFT analysis. J. Biomol. Struct. Dyn., 2015, 33(5), 978-990.
[http://dx.doi.org/10.1080/07391102.2014.921793] [PMID: 24805972]
[44]
Chadha, N.; Tiwari, A.K.; Kumar, V.; Milton, M.D.; Mishra, A.K. In silico thermodynamics stability change analysis involved in BH4 responsive mutations in phenylalanine hydroxylase: QM/MM and MD simulations analysis. J. Biomol. Struct. Dyn., 2015, 33(3), 573-583.
[http://dx.doi.org/10.1080/07391102.2014.897258] [PMID: 24628256]
[45]
Lu, S.Y.; Jiang, Y.J.; Lv, J.; Wu, T.X.; Yu, Q.S.; Zhu, W.L. Molecular docking and molecular dynamics simulation studies of GPR40 receptor-agonist interactions. J. Mol. Graph. Model., 2010, 28(8), 766-774.
[http://dx.doi.org/10.1016/j.jmgm.2010.02.001] [PMID: 20227312]
[46]
Rao, R.; Diharce, J.; Dugué, B.; Ostuni, M.A.; Cadet, F.; Etchebest, C. Versatile dimerisation process of translocator protein (TSPO) revealed by an extensive sampling based on a coarse-grained dynamics study. J. Chem. Inf. Model., 2020, 60(8), 3944-3957.
[http://dx.doi.org/10.1021/acs.jcim.0c00246] [PMID: 32697916]
[47]
Pike, V.W. Considerations in the development of reversibly binding PET radioligands for brain Imaging. Curr. Med. Chem., 2016, 23(18), 1818-1869.
[http://dx.doi.org/10.2174/0929867323666160418114826] [PMID: 27087244]

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