Abstract
Aims: To expound the mechanisms of selective PARP-1 inhibition by compound10n.
Background: Poly ADP-ribose polymerase-1 (PARP-1), due to its role in DNA damage and repair, has been identified as a crucial therapeutic target to attenuate cancer development and progression.
Objective: Selective inhibition has remained a focal point in PARP-1 targeting, therefore, we explored the selective inhibitory mechanism of Compound10n.
Methods: we employed computational methods for this study.
Results: Findings revealed that the inhibitor stabilized the characteristic motion of activated PARP- 1 as evidenced by reductions in residual deviations and structural flexibility. Findings further revealed that compound10n was favorably bound at the active site PARP-1 as supported by the occurrence of strong hydrogen and halogen bonds based on complementarity. These were in addition to aromatic bonds with enhanced ring to ring stability. Steady and high-affinity interactions between the fluorine atom of compound10n and Glu988 could potentiate the selective activity of the compound. Interaction analyses also revealed that inhibitor binding was strongly dependent on electrostatic effects over van der Waal contributions which were relatively minimal.
Conclusion: We believe findings from this study will further contribute to the rational structurebased design of highly selective PARP-1 inhibitors.
Keywords: Poly ADP-ribose polymerase-1, nicotinamide adenine dinucleotide, homoerythrina alkaloid derivative, cancer cells, MD simulation, MM/PBSA.
Graphical Abstract
[1]
Di Girolamo, M.; Fabrizio, G. The adp-ribosyl-transferases diphtheria toxin-like (ARTDs) Family: An overview. Challenges., 2018, 9(1), 24.
[http://dx.doi.org/10.3390/challe9010024]
[http://dx.doi.org/10.3390/challe9010024]
[2]
Gibson, B.A.; Kraus, W.L. New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat. Rev. Mol. Cell Biol., 2012, 13(7), 411-424.
[http://dx.doi.org/10.1038/nrm3376] [PMID: 22713970]
[http://dx.doi.org/10.1038/nrm3376] [PMID: 22713970]
[3]
Krishnakumar, R.; Kraus, W.L. New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Mol. Cell, 2010, 39(1), 8-24.
[http://dx.doi.org/10.1016/j.molcel.2010.06.017] [PMID: 20603072]
[http://dx.doi.org/10.1016/j.molcel.2010.06.017] [PMID: 20603072]
[4]
Bürkle, A. Poly(ADP-ribose). The most elaborate metabolite of NAD+. FEBS J., 2005, 272(18), 4576-4589.
[http://dx.doi.org/10.1111/j.1742-4658.2005.04864.x] [PMID: 16156780]
[http://dx.doi.org/10.1111/j.1742-4658.2005.04864.x] [PMID: 16156780]
[5]
Hottiger, M.O.; Hassa, P.O.; Lüscher, B.; Schüler, H.; Koch-Nolte, F. Toward a unified nomenclature for mammalian ADP-ribosyltransferases. Trends Biochem. Sci., 2010, 35(4), 208-219.
[http://dx.doi.org/10.1016/j.tibs.2009.12.003] [PMID: 20106667]
[http://dx.doi.org/10.1016/j.tibs.2009.12.003] [PMID: 20106667]
[6]
Yelamos, J.; Farres, J.; Llacuna, L.; Ampurdanes, C.; Martin-Caballero, J. PARP-1 and PARP-2: New players in tumour development. Am. J. Cancer Res., 2011, 1(3), 328-346.http://www.ncbi.nlm.nih.gov/pubmed/21968702%0Ahttp://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC3180065
[PMID: 21968702]
[PMID: 21968702]
[7]
Yélamos, J.; Schreiber, V.; Dantzer, F. Toward specific functions of poly(ADP-ribose) polymerase-2. Trends Mol. Med., 2008, 14(4), 169-178.
[http://dx.doi.org/10.1016/j.molmed.2008.02.003] [PMID: 18353725]
[http://dx.doi.org/10.1016/j.molmed.2008.02.003] [PMID: 18353725]
[8]
Papeo, G.; Orsini, P.; Avanzi, N.R.; Borghi, D.; Casale, E.; Ciomei, M.; Cirla, A.; Desperati, V.; Donati, D.; Felder, E.R.; Galvani, A.; Guanci, M.; Isacchi, A.; Posteri, H.; Rainoldi, S.; Riccardi-Sirtori, F.; Scolaro, A.; Montagnoli, A. Discovery of stereospecific PARP-1 inhibitor isoindolinone NMS-P515. ACS Med. Chem. Lett., 2019, 10(4), 534-538.
[http://dx.doi.org/10.1021/acsmedchemlett.8b00569] [PMID: 30996792]
[http://dx.doi.org/10.1021/acsmedchemlett.8b00569] [PMID: 30996792]
[9]
Bürkle, A.; Virág, L. Poly(ADP-ribose): PARadigms and PARadoxes. Mol. Aspects Med., 2013, 34(6), 1046-1065.
[http://dx.doi.org/10.1016/j.mam.2012.12.010] [PMID: 23290998]
[http://dx.doi.org/10.1016/j.mam.2012.12.010] [PMID: 23290998]
[10]
Lüscher, B.; Bütepage, M.; Eckei, L.; Krieg, S.; Verheugd, P.; Shilton, B.H. ADP-ribosylation, a multifaceted posttranslational modification involved in the control of cell physiology in health and disease. Chem. Rev., 2018, 118(3), 1092-1136.
[http://dx.doi.org/10.1021/acs.chemrev.7b00122] [PMID: 29172462]
[http://dx.doi.org/10.1021/acs.chemrev.7b00122] [PMID: 29172462]
[11]
Belousova, E.A.; Ishchenko, А.A.; Lavrik, O.I. DNA is a new target of Parp3. Sci. Rep., 2018, 8(1), 4176.
[http://dx.doi.org/10.1038/s41598-018-22673-3] [PMID: 29520010]
[http://dx.doi.org/10.1038/s41598-018-22673-3] [PMID: 29520010]
[12]
Talhaoui, I.; Lebedeva, N.A.; Zarkovic, G.; Saint-Pierre, C.; Kutuzov, M.M.; Sukhanova, M.V.; Matkarimov, B.T.; Gasparutto, D.; Saparbaev, M.K.; Lavrik, O.I.; Ishchenko, A.A. Poly(ADP-ribose) polymerases covalently modify strand break termini in DNA fragments in vitro. Nucleic Acids Res., 2016, 44(19), 9279-9295.
[PMID: 27471034]
[PMID: 27471034]
[13]
Sandhu, S.K.; Yap, T.A.; de Bono, J.S. Poly(ADP-ribose) polymerase inhibitors in cancer treatment: a clinical perspective. Eur. J. Cancer, 2010, 46(1), 9-20.
[http://dx.doi.org/10.1016/j.ejca.2009.10.021] [PMID: 19926276]
[http://dx.doi.org/10.1016/j.ejca.2009.10.021] [PMID: 19926276]
[14]
Langelier, M.F.; Ruhl, D.D.; Planck, J.L.; Kraus, W.L.; Pascal, J.M. The Zn3 domain of human poly(ADP-ribose) polymerase-1 (PARP-1) functions in both DNA-dependent poly(ADP-ribose) synthesis activity and chromatin compaction. J. Biol. Chem., 2010, 285(24), 18877-18887.
[http://dx.doi.org/10.1074/jbc.M110.105668] [PMID: 20388712]
[http://dx.doi.org/10.1074/jbc.M110.105668] [PMID: 20388712]
[15]
Langelier, M.F.; Servent, K.M.; Rogers, E.E.; Pascal, J.M. A third zinc-binding domain of human poly(ADP-ribose) polymerase-1 coordinates DNA-dependent enzyme activation. J. Biol. Chem., 2008, 283(7), 4105-4114.
[http://dx.doi.org/10.1074/jbc.M708558200] [PMID: 18055453]
[http://dx.doi.org/10.1074/jbc.M708558200] [PMID: 18055453]
[16]
Langelier, M.F.; Planck, J.L.; Roy, S.; Pascal, J.M.; Pascal, J.M. Structural basis for DNA damage-dependent poly(ADP-ribosyl)ation by human PARP-1. Science, 2012, 336(6082), 728-732.
[http://dx.doi.org/10.1126/science.1216338] [PMID: 22582261]
[http://dx.doi.org/10.1126/science.1216338] [PMID: 22582261]
[17]
Ye, N.; Chen, C.; Chen, T.T.; Song, Z.; He, J.; Huan, X. Design, synthesis and biological evaluation of a series of longer chain appendage as novel PARP1 inhibitors. J. Med. Chem., 2013, 56(7), 2885-2903.
[18]
Bryant, H.E.; Schultz, N.; Thomas, H.D.; Parker, K.M.; Flower, D.; Lopez, E.; Kyle, S.; Meuth, M.; Curtin, N.J.; Helleday, T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature, 2005, 434(7035), 913-917.
[http://dx.doi.org/10.1038/nature03443] [PMID: 15829966]
[http://dx.doi.org/10.1038/nature03443] [PMID: 15829966]
[19]
Curtin, N.J.; Szabo, C. Therapeutic applications of PARP inhibitors: anticancer therapy and beyond. Mol. Aspects Med., 2013, 34(6), 1217-1256.
[http://dx.doi.org/10.1016/j.mam.2013.01.006] [PMID: 23370117]
[http://dx.doi.org/10.1016/j.mam.2013.01.006] [PMID: 23370117]
[20]
Walsh, C. Targeted therapy for ovarian cancer: the rapidly evolving landscape of PARP inhibitor use. Minerva Ginecol., 2018, 70(2), 150-170.
[PMID: 28994564]
[PMID: 28994564]
[21]
Exman, P.; Barroso-Sousa, R.; Tolaney, S.M. Evidence to date: talazoparib in the treatment of breast cancer. OncoTargets Ther., 2019, 12, 5177-5187.
[http://dx.doi.org/10.2147/OTT.S184971] [PMID: 31303769]
[http://dx.doi.org/10.2147/OTT.S184971] [PMID: 31303769]
[22]
Ohmoto, A.; Yachida, S. Current status of poly(ADP-ribose) polymerase inhibitors and future directions. OncoTargets Ther., 2017, 10, 5195-5208.
[http://dx.doi.org/10.2147/OTT.S139336] [PMID: 29138572]
[http://dx.doi.org/10.2147/OTT.S139336] [PMID: 29138572]
[23]
Li, X.; Li, C.; Jin, J.; Wang, J.; Huang, J.; Ma, Z. High PARP-1 expression predicts poor survival in acute myeloid leukemia and PARP-1 inhibitor and SAHA-bendamustine hybrid inhibitor combination treatment synergistically enhances anti-tumor effects. EBio. Med., 2018, 38, 47-56.
[24]
Bourton, E.C.; Ahorner, P.A.; Plowman, P.N.; Zahir, S.A.; Al-Ali, H.; Parris, C.N. The PARP-1 inhibitor Olaparib suppresses BRCA1 protein levels, increases apoptosis and causes radiation hypersensitivity in BRCA1+/- lymphoblastoid cells. J. Cancer, 2017, 8(19), 4048-4056.
[http://dx.doi.org/10.7150/jca.21338] [PMID: 29187880]
[http://dx.doi.org/10.7150/jca.21338] [PMID: 29187880]
[25]
Almahli, H.; Hadchity, E.; Jaballah, M.Y.; Daher, R.; Ghabbour, H.A.; Kabil, M.M.; Al-Shakliah, N.S.; Eldehna, W.M. Development of novel synthesized phthalazinone-based PARP-1 inhibitors with apoptosis inducing mechanism in lung cancer. Bioorg. Chem., 2018, 77, 443-456.
[http://dx.doi.org/10.1016/j.bioorg.2018.01.034] [PMID: 29453076]
[http://dx.doi.org/10.1016/j.bioorg.2018.01.034] [PMID: 29453076]
[26]
Wang, Y.Q.; Wang, P.Y.; Wang, Y.T.; Yang, G.F.; Zhang, A.; Miao, Z.H. An update on poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors: Opportunities and challenges in cancer therapy. J. Med. Chem., 2016, 59(21), 9575-9598.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00055] [PMID: 27416328]
[http://dx.doi.org/10.1021/acs.jmedchem.6b00055] [PMID: 27416328]
[27]
Jain, P.G.; Patel, B.D. Medicinal chemistry approaches of poly ADP-Ribose polymerase 1 (PARP1) inhibitors as anticancer agents - A recent update. Eur. J. Med. Chem., 2019, 165, 198-215.
[http://dx.doi.org/10.1016/j.ejmech.2019.01.024] [PMID: 30684797]
[http://dx.doi.org/10.1016/j.ejmech.2019.01.024] [PMID: 30684797]
[28]
Li, S.; Li, X.Y.; Zhang, T.J.; Kamara, M.O.; Liang, J.W.; Zhu, J.; Meng, F.H. Design, synthesis and biological evaluation of homoerythrina alkaloid derivatives bearing a triazole moiety as PARP-1 inhibitors and as potential antitumor drugs. Bioorg. Chem., 2020, 94103385
[http://dx.doi.org/10.1016/j.bioorg.2019.103385] [PMID: 31669094]
[http://dx.doi.org/10.1016/j.bioorg.2019.103385] [PMID: 31669094]
[29]
Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera-a visualization system for exploratory research and analysis. J. Comput. Chem., 2004, 25(13), 1605-1612.
[http://dx.doi.org/10.1002/jcc.20084] [PMID: 15264254]
[http://dx.doi.org/10.1002/jcc.20084] [PMID: 15264254]
[30]
Webb, B Sali, A Comparative protein structure modeling using MODELLER. Curr. Protoc. Bioinforma, 2016. 54, 5.6.1-5.6.37
[31]
Hanwell, M.D.; Curtis, D.E.; Lonie, D.C.; Vandermeersch, T.; Zurek, E.; Hutchison, G.R. Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. J. Cheminform., 2012, 4(1), 17.
[http://dx.doi.org/10.1186/1758-2946-4-17] [PMID: 22889332]
[http://dx.doi.org/10.1186/1758-2946-4-17] [PMID: 22889332]
[32]
Allouche, A. Software news and updates gabedit - a graphical user interface for computational chemistry softwares. J. Comput. Chem., 2012, 32, 174-182.
[http://dx.doi.org/10.1002/jcc.21600] [PMID: 20607691]
[http://dx.doi.org/10.1002/jcc.21600] [PMID: 20607691]
[33]
Case, D.A.; Walker, R.C.; Cheatham, T.E.; Simmerling, C.; Roitberg, A.; Merz, K.M. Amber 18. Univ California, San Fr [Internet]. 2018. Available from:
http://ambermd.org/doc12/Amber18.pdf
[34]
Maier, J.A.; Martinez, C.; Kasavajhala, K.; Wickstrom, L.; Hauser, K.E.; Simmerling, C. ff14SB: Improving the accuracy of protein side chain and backbone parameters from ff99SB. J. Chem. Theory Comput., 2015, 11(8), 3696-3713.
[http://dx.doi.org/10.1021/acs.jctc.5b00255] [PMID: 26574453]
[http://dx.doi.org/10.1021/acs.jctc.5b00255] [PMID: 26574453]
[35]
Case, D.A.; Cheatham, T.E., III; Darden, T.; Gohlke, H.; Luo, R.; Merz, K.M., Jr; Onufriev, A.; Simmerling, C.; Wang, B.; Woods, R.J. The Amber biomolecular simulation programs. J. Comput. Chem., 2005, 26(16), 1668-1688.
[http://dx.doi.org/10.1002/jcc.20290] [PMID: 16200636]
[http://dx.doi.org/10.1002/jcc.20290] [PMID: 16200636]
[36]
Jorgensen, W.L.; Chandrasekhar, J.; Madura, J.D.; Impey, R.W.; Klein, M.L. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys., 1983, 79(2), 926-935.
[http://dx.doi.org/10.1063/1.445869]
[http://dx.doi.org/10.1063/1.445869]
[37]
Berendsen, H.J.C.; Postma, J.P.M.; Van Gunsteren, W.F.; Dinola, A.; Haak, J.R. Molecular dynamics with coupling to an external bath. J. Chem. Phys., 1984, 81(8), 3684-3690.
[http://dx.doi.org/10.1063/1.448118]
[http://dx.doi.org/10.1063/1.448118]
[38]
Roe, D.R.; Cheatham, T.E. III PTRAJ and CPPTRAJ: Software for processing and analysis of molecular dynamics trajectory data. J. Chem. Theory Comput., 2013, 9(7), 3084-3095.
[http://dx.doi.org/10.1021/ct400341p] [PMID: 26583988]
[http://dx.doi.org/10.1021/ct400341p] [PMID: 26583988]
[39]
Seifert, E. OriginPro 9.1: scientific data analysis and graphing software-software review. J. Chem. Inf. Model., 2014, 54(5), 1552.
[http://dx.doi.org/10.1021/ci500161d] [PMID: 24702057]
[http://dx.doi.org/10.1021/ci500161d] [PMID: 24702057]
[40]
David, C.C.; Jacobs, D.J. Principal component analysis: a method for determining the essential dynamics of proteins. Methods Mol. Biol., 2014, 1084, 193-226. Available from:
http://link.springer.com/10.1007/978-1-62703-658-0
[41]
Sittel, F.; Jain, A.; Stock, G. Principal component analysis of molecular dynamics: on the use of cartesian vs. internal coordinates. J. Chem. Phys., 2014, 141(1)014111
[http://dx.doi.org/10.1063/1.4885338] [PMID: 25005281]
[http://dx.doi.org/10.1063/1.4885338] [PMID: 25005281]
[42]
Mukherjee, J.; Gupta, M.N. Increasing importance of protein flexibility in designing biocatalytic processes. Biotechnol. Rep. (Amst.), 2015, 6, 119-123.
[http://dx.doi.org/10.1016/j.btre.2015.04.001] [PMID: 28626705]
[http://dx.doi.org/10.1016/j.btre.2015.04.001] [PMID: 28626705]
[43]
Olotu, F.A.; Soliman, M.E.S. From mutational inactivation to aberrant gain-of-function: Unraveling the structural basis of mutant p53 oncogenic transition. J. Cell. Biochem., 2018, 119(3), 2646-2652.
[http://dx.doi.org/10.1002/jcb.26430] [PMID: 29058783]
[http://dx.doi.org/10.1002/jcb.26430] [PMID: 29058783]
[44]
Soremekun, O.S.; Olotu, F.A.; Agoni, C.; Soliman, M.E.S. Drug promiscuity: Exploring the polypharmacology potential of 1, 3, 6-trisubstituted 1, 4-diazepane-7-ones as an inhibitor of the ‘god father’ of immune checkpoint. Comput. Biol. Chem., 2019, 80(March), 433-440.
[http://dx.doi.org/10.1016/j.compbiolchem.2019.05.009] [PMID: 31146119]
[http://dx.doi.org/10.1016/j.compbiolchem.2019.05.009] [PMID: 31146119]
[45]
Bös, F.; Pleiss, J. Multiple molecular dynamics simulations of TEM β-lactamase: dynamics and water binding of the omega-loop. Biophys. J., 2009, 97(9), 2550-2558.
[http://dx.doi.org/10.1016/j.bpj.2009.08.031] [PMID: 19883598]
[http://dx.doi.org/10.1016/j.bpj.2009.08.031] [PMID: 19883598]
[46]
Badichi Akher, F.; Farrokhzadeh, A.; Olotu, F.A.; Agoni, C.; Soliman, M.E.S. The irony of chirality - unveiling the distinct mechanistic binding and activities of 1-(3-(4-amino-5-(7-methoxy-5-methylbenzo[b]thiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one enantiomers as irreversible covalent FGFR4 inhibitors. Org. Biomol. Chem., 2019, 17(5), 1176-1190.
[http://dx.doi.org/10.1039/C8OB02811G] [PMID: 30644960]
[http://dx.doi.org/10.1039/C8OB02811G] [PMID: 30644960]
[47]
Halder, A.K.; Saha, A.; Saha, K.D.; Jha, T. Stepwise development of structure-activity relationship of diverse PARP-1 inhibitors through comparative and validated in silico modeling techniques and molecular dynamics simulation. J. Biomol. Struct. Dyn., 2015, 33(8), 1756-1779.
[http://dx.doi.org/10.1080/07391102.2014.969772] [PMID: 25350685]
[http://dx.doi.org/10.1080/07391102.2014.969772] [PMID: 25350685]
[48]
Nilov, D.; Maluchenko, N.; Kurgina, T.; Pushkarev, S.; Lys, A.; Kutuzov, M.; Gerasimova, N.; Feofanov, A.; Švedas, V.; Lavrik, O.; Studitsky, V.M. Molecular mechanisms of PARP-1 inhibitor 7-methylguanine. Int. J. Mol. Sci., 2020, 21(6), 1-11.
[http://dx.doi.org/10.3390/ijms21062159] [PMID: 32245127]
[http://dx.doi.org/10.3390/ijms21062159] [PMID: 32245127]
[49]
Salmas, R.E.; Unlu, A.; Yurtsever, M.; Noskov, S.Y.; Durdagi, S. In silico investigation of PARP-1 catalytic domains in holo and apo states for the design of high-affinity PARP-1 inhibitors. J. Enzyme Inhib. Med. Chem., 2016, 31(1), 112-120.
[http://dx.doi.org/10.3109/14756366.2015.1005011] [PMID: 26083304]
[http://dx.doi.org/10.3109/14756366.2015.1005011] [PMID: 26083304]
[50]
Manasaryan, GA; Kirsanov, K.I. Modeling of the enzyme – substrate complexes of human poly (ADP Ribose) polymerase 1. Biochemistry (Mosc.), 2020, 85(1), 99-107.
[51]
Xin, M.; Sun, J.; Huang, W.; Tang, F.; Liu, Z.; Jin, Q.; Wang, J. Design and synthesis of novel phthalazinone derivatives as potent poly(ADP-ribose)polymerase 1 inhibitors. Future Med. Chem., 2020, 12(19), 1691-1707.
[http://dx.doi.org/10.4155/fmc-2020-0009] [PMID: 33012191]
[http://dx.doi.org/10.4155/fmc-2020-0009] [PMID: 33012191]
[52]
Boraei, A.T.A.; Singh, P.K.; Sechi, M.; Satta, S. Discovery of novel functionalized 1,2,4-triazoles as PARP-1 inhibitors in breast cancer: Design, synthesis and antitumor activity evaluation. Eur. J. Med. Chem. 2019, 182, 111621
[http://dx.doi.org/10.1016/j.ejmech.2019.111621] [PMID: 31442685]
[http://dx.doi.org/10.1016/j.ejmech.2019.111621] [PMID: 31442685]
Article Metrics
13
1