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Current Computer-Aided Drug Design

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ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

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Research Article

Development of Potential Inhibitors for Human T-lymphotropic Virus Type I Integrase Enzyme: A Molecular Modeling Approach

Author(s): Mohammad Jalili-Nik, Arash Soltani, Seyed Isaac Hashemy, Houshang Rafatpanah, Seyed Abdolrahim Rezaee, Ali Gorji, Renate Griffith and Baratali Mashkani*

Volume 20, Issue 1, 2024

Published on: 08 May, 2023

Page: [72 - 86] Pages: 15

DOI: 10.2174/1573409919666230419082839

Price: $65

Abstract

Introduction: Integration of viral DNA into the host cell genome, carried out by the HTLV-1 integrase enzyme, is a crucial step in the Human T-lymphotropic Virus type I (HTLV-1) life cycle. Thus, HTLV-1 integrase is considered an attractive therapeutic target; however, no clinically effective inhibitors are available to treat HTLV-1 infection.

Objective: The main objective was to identify potential drug-like compounds capable of effectively inhibiting HTLV-1 integrase activity.

Methods: In this study, a model of HTLV-1 integrase structure and three integrase inhibitors (dolutegravir, raltegravir, and elvitegravir as scaffolds) were used for designing new inhibitors. Designed molecules were used as templates for virtual screening to retrieve new inhibitors from PubChem, ZINC15, and ChEMBL databases. Drug-likeness and docked energy of the molecules were investigated using the SWISS-ADME portal and GOLD software. Stability and binding energy of the complexes were further investigated using molecular dynamic (MD) simulation.

Results: Four novel potential inhibitors were developed using a structure-based design protocol and three compounds from virtual screening. They formed hydrogen bonding interactions with critical residues Asp69, Asp12, Tyr96, Tyr143, Gln146, Ile13, and Glu105. In addition, π stacking, halogen, and hydrogen bond interactions were seen between compounds (especially halogenated benzyl moieties) and viral DNA similar to those seen in parent molecules. MD simulation confirmed higher stability of the receptor-ligand complex than the ligand-free enzyme.

Conclusion: Combing structure-based design and virtual screening resulted in identifying three drug-like molecules (PubChem CID_138739497, _70381610, and _140084032) that are suggested as lead compounds for developing effective drugs targeting HTLV-1 integrase enzyme.

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[1]
Bhatt, V.; Shi, K.; Salamango, D.J.; Moeller, N.H.; Pandey, K.K.; Bera, S.; Bohl, H.O.; Kurniawan, F.; Orellana, K.; Zhang, W.; Grandgenett, D.P.; Harris, R.S.; Sundborger-Lunna, A.C.; Aihara, H. Structural basis of host protein hijacking in human T-cell leukemia virus integration. Nat. Commun., 2020, 11(1), 3121.
[http://dx.doi.org/10.1038/s41467-020-16963-6] [PMID: 32561747]
[2]
Kanki, P.J.; Hopper, J.R.; Essex, M. The Origins of HIV-1 and HTLV-4/HIV-2. Ann. N. Y. Acad. Sci., 1987, 511(1), 370-375.
[http://dx.doi.org/10.1111/j.1749-6632.1987.tb36265.x] [PMID: 2894192]
[3]
Gallo, R.C. History of the discoveries of the first human retroviruses: HTLV-1 and HTLV-2. Oncogene, 2005, 24(39), 5926-5930.
[http://dx.doi.org/10.1038/sj.onc.1208980] [PMID: 16155599]
[4]
Eusebio-Ponce, E.; Anguita, E.; Paulino-Ramirez, R.; Candel, F.J. HTLV-1 infection: An emerging risk. Pathogenesis, epidemiology, diagnosis and associated diseases. Rev. Esp. Quimioter., 2019, 32(6), 485-496.
[PMID: 31648512]
[5]
Rosadas, C.; Assone, T.; Yamashita, M.; Adonis, A.; Puccioni-Sohler, M.; Santos, M.; Paiva, A.; Casseb, J.; Oliveira, A.C.P.; Taylor, G.P. Health state utility values in people living with HTLV-1 and in patients with HAM/TSP: The impact of a neglected disease on the quality of life. PLoS Negl. Trop. Dis., 2020, 14(10), e0008761.
[http://dx.doi.org/10.1371/journal.pntd.0008761] [PMID: 33064742]
[6]
Marino-Merlo, F.; Mastino, A.; Grelli, S.; Hermine, O.; Bazarbachi, A.; Macchi, B. Future perspectives on drug targeting in adult T cell leukemia-lymphoma. Front. Microbiol., 2018, 9, 925.
[http://dx.doi.org/10.3389/fmicb.2018.00925] [PMID: 29867836]
[7]
Watanabe, T.; Tobinai, K.; Shibata, T.; Tsukasaki, K.; Morishima, Y.; Maseki, N.; Kinoshita, T.; Suzuki, T.; Yamaguchi, M.; Ando, K.; Ogura, M.; Taniwaki, M.; Uike, N.; Takeuchi, K.; Nawano, S.; Terauchi, T.; Hotta, T. Phase II/III study of R-CHOP-21 versus R-CHOP-14 for untreated indolent B-cell non-Hodgkin’s lymphoma: JCOG 0203 trial. J. Clin. Oncol., 2011, 29(30), 3990-3998.
[http://dx.doi.org/10.1200/JCO.2011.34.8508] [PMID: 21931035]
[8]
Jalili-Nik, M.; Soltani, A.; Mashkani, B.; Rafatpanah, H.; Hashemy, S.I. PD-1 and PD-L1 inhibitors foster the progression of adult T-cell Leukemia/Lymphoma. Int. Immunopharmacol., 2021, 98, 107870.
[http://dx.doi.org/10.1016/j.intimp.2021.107870] [PMID: 34153661]
[9]
Laydon, D.J.; Sunkara, V.; Boelen, L.; Bangham, C.R.M.; Asquith, B. The relative contributions of infectious and mitotic spread to HTLV-1 persistence. PLOS Comput. Biol., 2020, 16(9), e1007470.
[http://dx.doi.org/10.1371/journal.pcbi.1007470] [PMID: 32941445]
[10]
Carneiro-Proietti, A.B.; Amaranto-Damasio, M.S.; Leal-Horiguchi, C.F.; Bastos, R.H.; Seabra-Freitas, G.; Borowiak, D.R.; Ribeiro, M.A.; Proietti, F.A.; Ferreira, A.S.; Martins, M.L. Mother-to-child transmission of human T-cell lymphotropic viruses-1/2: What we know, and what are the gaps in understanding and preventing this route of infection. J. Pediatric Infect. Dis. Soc., 2014, 3(S1), 24-29.
[11]
Marino-Merlo, F.; Balestrieri, E.; Matteucci, C.; Mastino, A.; Grelli, S.; Macchi, B. Antiretroviral therapy in HTLV-1 infection: An updated overview. Pathogens, 2020, 9(5), 342.
[http://dx.doi.org/10.3390/pathogens9050342] [PMID: 32369988]
[12]
Komal, D.; Khushboo, J.; Aaftaab, S.; Lakshmi, S.; Mallika, A. Targeting Integrase Enzyme: A therapeutic approach to combat HIV resistance. Mini Rev. Med. Chem., 2020, 20(3), 219-238.
[http://dx.doi.org/10.2174/1389557519666191015124932] [PMID: 31613727]
[13]
Brooks, K.M.; Sherman, E.M.; Egelund, E.F.; Brotherton, A.; Durham, S.; Badowski, M.E.; Cluck, D.B. Integrase inhibitors: after 10 years of experience, is the best yet to come? Pharmacotherapy, 2019, 39(5), 576-598.
[http://dx.doi.org/10.1002/phar.2246] [PMID: 30860610]
[14]
Barski, M.S.; Minnell, J.J.; Maertens, G.N. Inhibition of HTLV-1 infection by HIV-1 first and second-generation integrase strand transfer inhibitors. Front. Microbiol., 2019, 10, 1877.
[http://dx.doi.org/10.3389/fmicb.2019.01877] [PMID: 31474960]
[15]
Lockbaum, G.J.; Henes, M.; Talledge, N.; Rusere, L.N.; Kosovrasti, K.; Nalivaika, E.A.; Somasundaran, M.; Ali, A.; Mansky, L.M.; Kurt Yilmaz, N.; Schiffer, C.A. Inhibiting HTLV-1 Protease: A viable antiviral target. ACS Chem. Biol., 2021, 16(3), 529-538.
[http://dx.doi.org/10.1021/acschembio.0c00975] [PMID: 33619959]
[16]
Jorgensen, W.L. Computer-aided discovery of anti-HIV agents. Bioorg. Med. Chem., 2016, 24(20), 4768-4778.
[http://dx.doi.org/10.1016/j.bmc.2016.07.039] [PMID: 27485603]
[17]
Vyas, V.K.; Ukawala, R.D.; Chintha, C.; Ghate, M. Homology modeling a fast tool for drug discovery: Current perspectives. Indian J. Pharm. Sci., 2012, 74(1), 1-17.
[http://dx.doi.org/10.4103/0250-474X.102537] [PMID: 23204616]
[18]
Muhammed, M.T.; Aki-Yalcin, E. Homology modeling in drug discovery: Overview, current applications, and future perspectives. Chem. Biol. Drug Des., 2019, 93(1), 12-20.
[http://dx.doi.org/10.1111/cbdd.13388] [PMID: 30187647]
[19]
Barski, M.S.; Vanzo, T.; Zhao, X.Z.; Smith, S.J.; Ballandras-Colas, A.; Cronin, N.B.; Pye, V.E.; Hughes, S.H.; Burke, T.R., Jr; Cherepanov, P.; Maertens, G.N. Structural basis for the inhibition of HTLV-1 integration inferred from cryo-EM deltaretroviral intasome structures. Nat. Commun., 2021, 12(1), 4996.
[http://dx.doi.org/10.1038/s41467-021-25284-1] [PMID: 34404793]
[20]
Burley, S.K.; Berman, H.M.; Kleywegt, G.J.; Markley, J.L.; Nakamura, H.; Velankar, S. Protein data bank (PDB): The single global macromolecular structure archive. Methods Mol. Biol., 2017, 1607, 627-641.
[http://dx.doi.org/10.1007/978-1-4939-7000-1_26] [PMID: 28573592]
[21]
Šali, A.; Blundell, T.L. Comparative protein modelling by satisfaction of spatial restraints. J. Mol. Biol., 1993, 234(3), 779-815.
[http://dx.doi.org/10.1006/jmbi.1993.1626] [PMID: 8254673]
[22]
Bhattacharya, D.; Nowotny, J.; Cao, R.; Cheng, J. 3Drefine: an interactive web server for efficient protein structure refinement. Nucleic Acids Res., 2016, 44(W1), W406-W409.
[http://dx.doi.org/10.1093/nar/gkw336] [PMID: 27131371]
[23]
Emsley, P.; Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr., 2004, 60(12), 2126-2132.
[http://dx.doi.org/10.1107/S0907444904019158]
[24]
Morris, A.L.; MacArthur, M.W.; Hutchinson, E.G.; Thornton, J.M. Stereochemical quality of protein structure coordinates. Proteins, 1992, 12(4), 345-364.
[http://dx.doi.org/10.1002/prot.340120407] [PMID: 1579569]
[25]
Joy, S.; Nair, P.S.; Hariharan, R.; Pillai, M.R. Detailed comparison of the protein-ligand docking efficiencies of GOLD, a commercial package and ArgusLab, a licensable freeware. In Silico Biol., 2006, 6(6), 601-605.
[PMID: 17518767]
[26]
Nurisso, A.; Bravo, J.; Carrupt, P.A.; Daina, A. Molecular docking using the molecular lipophilicity potential as hydrophobic descriptor: Impact on GOLD docking performance. J. Chem. Inf. Model., 2012, 52(5), 1319-1327.
[http://dx.doi.org/10.1021/ci200515g] [PMID: 22462609]
[27]
Kim, S.; Thiessen, P.A.; Bolton, E.E.; Chen, J.; Fu, G.; Gindulyte, A.; Han, L.; He, J.; He, S.; Shoemaker, B.A.; Wang, J.; Yu, B.; Zhang, J.; Bryant, S.H. PubChem substance and compound databases. Nucleic Acids Res., 2016, 44(D1), D1202-D1213.
[http://dx.doi.org/10.1093/nar/gkv951] [PMID: 26400175]
[28]
Böhm, H.J. The computer program LUDI: a new method for the de novo design of enzyme inhibitors. J. Comput. Aided Mol. Des., 1992, 6(1), 61-78.
[http://dx.doi.org/10.1007/BF00124387] [PMID: 1583540]
[29]
Kim, S.; Chen, J.; Cheng, T.; Gindulyte, A.; He, J.; He, S.; Li, Q.; Shoemaker, B.A.; Thiessen, P.A.; Yu, B.; Zaslavsky, L.; Zhang, J.; Bolton, E.E. PubChem in 2021: New data content and improved web interfaces. Nucleic Acids Res., 2021, 49(D1), D1388-D1395.
[http://dx.doi.org/10.1093/nar/gkaa971] [PMID: 33151290]
[30]
Mendez, D.; Gaulton, A.; Bento, A.P.; Chambers, J.; De Veij, M.; Félix, E.; Magariños, M.P.; Mosquera, J.F.; Mutowo, P.; Nowotka, M.; Gordillo-Marañón, M.; Hunter, F.; Junco, L.; Mugumbate, G.; Rodriguez-Lopez, M.; Atkinson, F.; Bosc, N.; Radoux, C.J.; Segura-Cabrera, A.; Hersey, A.; Leach, A.R. ChEMBL: towards direct deposition of bioassay data. Nucleic Acids Res., 2019, 47(D1), D930-D940.
[http://dx.doi.org/10.1093/nar/gky1075] [PMID: 30398643]
[31]
Sterling, T.; Irwin, J.J. ZINC 15 - Ligand discovery for everyone. J. Chem. Inf. Model., 2015, 55(11), 2324-2337.
[http://dx.doi.org/10.1021/acs.jcim.5b00559] [PMID: 26479676]
[32]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7(1), 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[33]
Abdelrheem, D.A.; Ahmed, S.A.; Abd El-Mageed, H.R.; Mohamed, H.S.; Rahman, A.A.; Elsayed, K.N.M.; Ahmed, S.A. The inhibitory effect of some natural bioactive compounds against SARS-CoV-2 main protease: insights from molecular docking analysis and molecular dynamic simulation. J. Environ. Sci. Health Part A Tox. Hazard. Subst. Environ. Eng., 2020, 55(11), 1373-1386.
[http://dx.doi.org/10.1080/10934529.2020.1826192] [PMID: 32998618]
[34]
Zhu, B.T.; Wang, P.; Nagai, M.; Wen, Y.; Bai, H.W. Inhibition of human catechol-O-methyltransferase (COMT)-mediated O-methylation of catechol estrogens by major polyphenolic components present in coffee. J. Steroid Biochem. Mol. Biol., 2009, 113(1-2), 65-74.
[http://dx.doi.org/10.1016/j.jsbmb.2008.11.011] [PMID: 19095062]
[35]
Cava, C.; Bertoli, G.; Castiglioni, I. Potential drugs against COVID-19 revealed by gene expression profile, molecular docking and molecular dynamic simulation. Future Virol., 2021, 16(8), 527-542.
[http://dx.doi.org/10.2217/fvl-2020-0392] [PMID: 34306168]
[36]
Krishnan, L.; Li, X.; Naraharisetty, H.L.; Hare, S.; Cherepanov, P.; Engelman, A. Structure-based modeling of the functional HIV-1 intasome and its inhibition. Proc. Natl. Acad. Sci. USA, 2010, 107(36), 15910-15915.
[http://dx.doi.org/10.1073/pnas.1002346107] [PMID: 20733078]
[37]
Passos, D.O.; Li, M.; Jóźwik, I.K.; Zhao, X.Z.; Santos-Martins, D.; Yang, R.; Smith, S.J.; Jeon, Y.; Forli, S.; Hughes, S.H.; Burke, T.R. Jr; Craigie, R.; Lyumkis, D. Structural basis for strand-transfer inhibitor binding to HIV intasomes. Science, 2020, 367(6479), 810-814.
[http://dx.doi.org/10.1126/science.aay8015] [PMID: 32001521]
[38]
Cook, N.J.; Li, W.; Berta, D.; Badaoui, M.; Ballandras-Colas, A.; Nans, A.; Kotecha, A.; Rosta, E.; Engelman, A.N.; Cherepanov, P. Structural basis of second-generation HIV integrase inhibitor action and viral resistance. Science, 2020, 367(6479), 806-810.
[http://dx.doi.org/10.1126/science.aay4919] [PMID: 32001525]
[39]
Miri, L.; Bouvier, G.; Kettani, A.; Mikou, A.; Wakrim, L.; Nilges, M.; Malliavin, T.E. Stabilization of the integrase-DNA complex by Mg 2+ ions and prediction of key residues for binding HIV-1 integrase inhibitors. Proteins, 2014, 82(3), 466-478.
[http://dx.doi.org/10.1002/prot.24412] [PMID: 24038133]
[40]
Van Drie, J.H.; Tong, L. Cryo-EM as a powerful tool for drug discovery. Bioorg. Med. Chem. Lett., 2020, 30(22), 127524.
[http://dx.doi.org/10.1016/j.bmcl.2020.127524] [PMID: 32890683]
[41]
Subramaniam, S.; Earl, L.A.; Falconieri, V.; Milne, J.L.S.; Egelman, E.H. Resolution advances in cryo-EM enable application to drug discovery. Curr. Opin. Struct. Biol., 2016, 41, 194-202.
[http://dx.doi.org/10.1016/j.sbi.2016.07.009] [PMID: 27552081]
[42]
Eldridge, M.D.; Murray, C.W.; Auton, T.R.; Paolini, G.V.; Mee, R.P. Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes. J. Comput. Aided Mol. Des., 1997, 11(5), 425-445.
[http://dx.doi.org/10.1023/A:1007996124545] [PMID: 9385547]
[43]
Murray, C.W.; Auton, T.R.; Eldridge, M.D. Empirical scoring functions. II. The testing of an empirical scoring function for the prediction of ligand-receptor binding affinities and the use of Bayesian regression to improve the quality of the model. J. Comput. Aided Mol. Des., 1998, 12(5), 503-519.
[http://dx.doi.org/10.1023/A:1008040323669] [PMID: 9834910]
[44]
Schulz-Gasch, T.; Stahl, M. Binding site characteristics in structure-based virtual screening: evaluation of current docking tools. J. Mol. Model., 2003, 9(1), 47-57.
[http://dx.doi.org/10.1007/s00894-002-0112-y] [PMID: 12638011]
[45]
Fong, P.; Wong, H.K. Evaluation of scoring function performance on DNA-ligand complexes. Open Med. Chem. J., 2019, 13(1), 40-49.
[http://dx.doi.org/10.2174/1874104501913010040]
[46]
Bar-Magen, T.; Sloan, R.D.; Donahue, D.A.; Kuhl, B.D.; Zabeida, A.; Xu, H.; Oliveira, M.; Hazuda, D.J.; Wainberg, M.A. Identification of novel mutations responsible for resistance to MK-2048, a second-generation HIV-1 integrase inhibitor. J. Virol., 2010, 84(18), 9210-9216.
[http://dx.doi.org/10.1128/JVI.01164-10] [PMID: 20610719]
[47]
Temesgen, Z.; Siraj, D.S. Raltegravir: First in class HIV integrase inhibitor. Ther. Clin. Risk Manag., 2008, 4(2), 493-500.
[http://dx.doi.org/10.2147/TCRM.S2268] [PMID: 18728839]
[48]
Underwood, M.R.; Johns, B.A.; Sato, A.; Martin, J.N.; Deeks, S.G.; Fujiwara, T. The activity of the integrase inhibitor dolutegravir against HIV-1 variants isolated from raltegravir-treated adults. J. Acquir. Immune Defic. Syndr., 2012, 61(3), 297-301.
[http://dx.doi.org/10.1097/QAI.0b013e31826bfd02] [PMID: 22878423]
[49]
Smith, S.J.; Zhao, X.Z.; Burke, T.R., Jr; Hughes, S.H. HIV-1 Integrase inhibitors that are broadly effective against drug-resistant mutants. Antimicrob. Agents Chemother., 2018, 62(9), e01035-e18.
[http://dx.doi.org/10.1128/AAC.01035-18] [PMID: 29987149]
[50]
Chen, D.; Oezguen, N.; Urvil, P.; Ferguson, C.; Dann, S.M.; Savidge, T.C. Regulation of protein-ligand binding affinity by hydrogen bond pairing. Sci. Adv., 2016, 2(3), e1501240.
[http://dx.doi.org/10.1126/sciadv.1501240] [PMID: 27051863]
[51]
Kuck, D.; Singh, N.; Lyko, F.; Medina-Franco, J.L. Novel and selective DNA methyltransferase inhibitors: Docking-based virtual screening and experimental evaluation. Bioorg. Med. Chem., 2010, 18(2), 822-829.
[http://dx.doi.org/10.1016/j.bmc.2009.11.050] [PMID: 20006515]
[52]
Pierri, C.L.; Parisi, G.; Porcelli, V. Computational approaches for protein function prediction: A combined strategy from multiple sequence alignment to molecular docking-based virtual screening. Biochim. Biophys. Acta. Proteins Proteomics, 2010, 1804(9), 1695-1712.
[http://dx.doi.org/10.1016/j.bbapap.2010.04.008] [PMID: 20433957]
[53]
Jenwitheesuk, E.; Samudrala, R. Virtual screening of HIV-1 protease inhibitors against human cytomegalovirus protease using docking and molecular dynamics. AIDS, 2005, 19(5), 529-531.
[http://dx.doi.org/10.1097/01.aids.0000162343.96674.4c] [PMID: 15764860]
[54]
Ripphausen, P.; Nisius, B.; Bajorath, J. State-of-the-art in ligand-based virtual screening. Drug Discov. Today, 2011, 16(9-10), 372-376.
[http://dx.doi.org/10.1016/j.drudis.2011.02.011] [PMID: 21349346]
[55]
Zhang, M.Q.; Wilkinson, B. Drug discovery beyond the ‘rule-of-five’. Curr. Opin. Biotechnol., 2007, 18(6), 478-488.
[http://dx.doi.org/10.1016/j.copbio.2007.10.005] [PMID: 18035532]
[56]
Collier, T.A.; Piggot, T.J.; Allison, J.R. Molecular dynamics simulation of proteins.Protein Nanotechnology: Protocols, Instrumentation, and Applications; Gerrard, J.A.; Domigan, L.J., Eds.; Springer US: New York, NY, 2020, pp. 311-327.
[http://dx.doi.org/10.1007/978-1-4939-9869-2_17]
[57]
Sargsyan, K.; Grauffel, C.; Lim, C. How molecular size impacts RMSD applications in molecular dynamics simulations. J. Chem. Theory Comput., 2017, 13(4), 1518-1524.
[http://dx.doi.org/10.1021/acs.jctc.7b00028] [PMID: 28267328]

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