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Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Recent Advances in Computer-aided Antiviral Drug Design Targeting HIV-1 Integrase and Reverse Transcriptase Associated Ribonuclease H

Author(s): Fengyuan Yang, Jingyi Yang, Zhao Zhang, Gao Tu, Xiaojun Yao, Weiwei Xue* and Feng Zhu*

Volume 29, Issue 10, 2022

Published on: 08 July, 2021

Page: [1664 - 1676] Pages: 13

DOI: 10.2174/0929867328666210708090123

Price: $65

Abstract

Acquired immunodeficiency syndrome (AIDS) has been a chronic, life-threatening disease for a long time. Though, a broad range of antiretroviral drug regimens is applicable for the successful suppression of virus replication in human immunodeficiency virus type 1 (HIV-1) infected people. The mutation-induced drug resistance problems during the treatment of AIDS forced people to continuously look for new antiviral agents. HIV-1 integrase (IN) and reverse transcriptase associated ribonuclease (RT-RNase H), two pivotal enzymes in HIV-1 replication progress, have gained popularity as druggable targets for designing novel HIV-1 antiviral drugs. During the development of HIV-1 IN and/or RT-RNase H inhibitors, computer-aided drug design (CADD), including homology modeling, pharmacophore, docking, molecular dynamics (MD) simulation and binding free energy calculation, represent a significant tool to accelerate the discovery of new drug candidates and reduce costs in antiviral drug development. In this review, we summarized the recent advances in the design of single- and dual-target inhibitors against HIV-1 IN or/and RT-RNase H as well as the prediction of mutation-induced drug resistance based on computational methods. We highlighted the results of the reported literatures and proposed some perspectives on the design of novel and more effective antiviral drugs in the future.

Keywords: HIV-1 integrase, reverse transcriptase associated ribonuclease H, computer-aided drug design, drug resistance prediction, molecular dynamics, antiviral drugs.

[2]
Choi, E.; Mallareddy, J.R.; Lu, D.; Kolluru, S. Recent advances in the discovery of small-molecule inhibitors of HIV-1 integrase. Future Sci. OA, 2018, 4(9), FSO338.
[http://dx.doi.org/10.4155/fsoa-2018-0060] [PMID: 30416746]
[3]
Bushman, F.D.F.; Fujiwara, T.; Craigie, R. Retroviral DNA integration directed by HIV integration protein in vitro. Science, 1990, 249(4976), 1555-1558.
[http://dx.doi.org/10.1126/science.2171144] [PMID: 2171144]
[4]
Asante-Appiah, E.; Skalka, A.M. HIV-1 integrase: structural organization, conformational changes, and catalysis. Adv. Virus Res., 1999, 52, 351-369.
[http://dx.doi.org/10.1016/S0065-3527(08)60306-1] [PMID: 10384242]
[5]
Elliot, E.; Chirwa, M.; Boffito, M. How recent findings on the pharmacokinetics and pharmacodynamics of integrase inhibitors can inform clinical use. Curr. Opin. Infect. Dis., 2017, 30(1), 58-73.
[http://dx.doi.org/10.1097/QCO.0000000000000327] [PMID: 27798496]
[6]
Siwe-Noundou, X.; Musyoka, T.M.; Moses, V.; Ndinteh, D.T.; Mnkandhla, D.; Hoppe, H.; Tastan Bishop, Ö.; Krause, R.W.M. Anti-HIV-1 integrase potency of methylgallate from alchornea cordifolia using in vitro and in silico approaches. Sci. Rep., 2019, 9(1), 4718.
[http://dx.doi.org/10.1038/s41598-019-41403-x] [PMID: 30886338]
[7]
Anstett, K.; Brenner, B.; Mesplede, T.; Wainberg, M.A. HIV drug resistance against strand transfer integrase inhibitors. Retrovirology, 2017, 14(1), 36.
[http://dx.doi.org/10.1186/s12977-017-0360-7] [PMID: 28583191]
[8]
Smith, S.J.Z.; Zhao, X.Z.; Burke, T.R., Jr; Hughes, S.H. Efficacies of cabotegravir and bictegravir against drug-resistant HIV-1 integrase mutants. Retrovirology, 2018, 15(1), 37.
[http://dx.doi.org/10.1186/s12977-018-0420-7] [PMID: 29769116]
[10]
Tsiang, M.; Jones, G.S.; Goldsmith, J.; Mulato, A.; Hansen, D.; Kan, E.; Tsai, L.; Bam, R.A.; Stepan, G.; Stray, K.M.; Niedziela-Majka, A.; Yant, S.R.; Yu, H.; Kukolj, G.; Cihlar, T.; Lazerwith, S.E.; White, K.L.; Jin, H. Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 Integrase Strand Transfer Inhibitor with an improved resistance profile. Antimicrob. Agents Chemother., 2016, 60(12), 7086-7097.
[http://dx.doi.org/10.1128/AAC.01474-16] [PMID: 27645238]
[11]
Mesplède, T.; Wainberg, M.A. Resistance against integrase strand transfer inhibitors and relevance to hiv persistence. Viruses, 2015, 7(7), 3703-3718.
[http://dx.doi.org/10.3390/v7072790] [PMID: 26198244]
[12]
Scarsi, K.K.H.; Havens, J.P.; Podany, A.T.; Avedissian, S.N.; Fletcher, C.V. HIV-1 integrase inhibitors: A comparative review of efficacy and safety. Drugs, 2020, 80(16), 1649-1676.
[http://dx.doi.org/10.1007/s40265-020-01379-9] [PMID: 32860583]
[13]
Brenner, B.G.T.; Thomas, R.; Blanco, J.L.; Ibanescu, R.I.; Oliveira, M.; Mesplède, T.; Golubkov, O.; Roger, M.; Garcia, F.; Martinez, E.; Wainberg, M.A. Development of a G118R mutation in HIV-1 integrase following a switch to dolutegravir monotherapy leading to cross-resistance to integrase inhibitors. J. Antimicrob. Chemother., 2016, 71(7), 1948-1953.
[http://dx.doi.org/10.1093/jac/dkw071] [PMID: 27029845]
[14]
Cahn, P.; Pozniak, A.L.; Mingrone, H.; Shuldyakov, A.; Brites, C.; Andrade-Villanueva, J.F.; Richmond, G.; Buendia, C.B.; Fourie, J.; Ramgopal, M.; Hagins, D.; Felizarta, F.; Madruga, J.; Reuter, T.; Newman, T.; Small, C.B.; Lombaard, J.; Grinsztejn, B.; Dorey, D.; Underwood, M.; Griffith, S.; Min, S. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: Week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet, 2013, 382(9893), 700-708.
[http://dx.doi.org/10.1016/S0140-6736(13)61221-0] [PMID: 23830355]
[15]
Lepik, K.J.H.; Harrigan, P.R.; Yip, B.; Wang, L.; Robbins, M.A.; Zhang, W.W.; Toy, J.; Akagi, L.; Lima, V.D.; Guillemi, S.; Montaner, J.S.G.; Barrios, R. Emergent drug resistance with integrase strand transfer inhibitor-based regimens. AIDS, 2017, 31(10), 1425-1434.
[http://dx.doi.org/10.1097/QAD.0000000000001494] [PMID: 28375875]
[16]
Wijting, I.E.A.; Lungu, C.; Rijnders, B.J.A.; van der Ende, M.E.; Pham, H.T.; Mesplede, T.; Pas, S.D.; Voermans, J.J.C.; Schuurman, R.; van de Vijver, D.A.M.C.; Boers, P.H.M.; Gruters, R.A.; Boucher, C.A.B.; van Kampen, J.J.A. HIV-1 resistance dynamics in patients with virologic failure to dolutegravir maintenance monotherapy. J. Infect. Dis., 2018, 218(5), 688-697.
[http://dx.doi.org/10.1093/infdis/jiy176] [PMID: 29617822]
[17]
Wang, X.; Gao, P.; Menendez-Arias, L.; Liu, X.; Zhan, P. Update on recent developments in small molecular HIV-1 RNase H inhibitors (2013-2016): Opportunities and challenges. Curr. Med. Chem., 2018, 25(14), 1682-1702.
[http://dx.doi.org/10.2174/0929867324666170113110839] [PMID: 28088905]
[18]
Corona, A.; Masaoka, T.; Tocco, G.; Tramontano, E.; Le Grice, S.F. Active site and allosteric inhibitors of the ribonuclease H activity of HIV reverse transcriptase. Future Med. Chem., 2013, 5(18), 2127-2139.
[http://dx.doi.org/10.4155/fmc.13.178] [PMID: 24261890]
[19]
Tramontano, E.; Di Santo, R. HIV-1 RT-associated RNase H function inhibitors: Recent advances in drug development. Curr. Med. Chem., 2010, 17(26), 2837-2853.
[http://dx.doi.org/10.2174/092986710792065045] [PMID: 20858167]
[20]
Ilina, T.; Labarge, K.; Sarafianos, S.G.; Ishima, R.; Parniak, M.A. Inhibitors of HIV-1 reverse transcriptase-associated ribonuclease H activity. Biology (Basel), 2012, 1(3), 521-541.
[http://dx.doi.org/10.3390/biology1030521] [PMID: 23599900]
[21]
Andréola, M.L.D.S.; De Soultrait, V.R.; Fournier, M.; Parissi, V.; Desjobert, C.; Litvak, S. HIV-1 integrase and RNase H activities as therapeutic targets. Expert Opin. Ther. Targets, 2002, 6(4), 433-446.
[http://dx.doi.org/10.1517/14728222.6.4.433] [PMID: 12223059]
[22]
Yang, F.; Zheng, G.; Fu, T.; Li, X.; Tu, G.; Li, Y.H.; Yao, X.; Xue, W.; Zhu, F. Prediction of the binding mode and resistance profile for a dual-target pyrrolyl diketo acid scaffold against HIV-1 integrase and reverse-transcriptase-associated ribonuclease H. Phys. Chem. Chem. Phys., 2018, 20(37), 23873-23884.
[http://dx.doi.org/10.1039/C8CP01843J] [PMID: 29947629]
[23]
Gill, M.S.A.; Hassan, S.S.; Ahemad, N. Evolution of HIV-1 reverse transcriptase and integrase dual inhibitors: Recent advances and developments. Eur. J. Med. Chem., 2019, 179, 423-448.
[http://dx.doi.org/10.1016/j.ejmech.2019.06.058] [PMID: 31265935]
[24]
Su, M.; Tan, J.; Lin, C.Y. Development of HIV-1 integrase inhibitors: Recent molecular modeling perspectives. Drug Discov. Today, 2015, 20(11), 1337-1348.
[http://dx.doi.org/10.1016/j.drudis.2015.07.012] [PMID: 26220090]
[25]
Liao, C.; Nicklaus, M.C. Computer tools in the discovery of HIV-1 integrase inhibitors. Future Med. Chem., 2010, 2(7), 1123-1140.
[http://dx.doi.org/10.4155/fmc.10.193] [PMID: 21426160]
[26]
Samorlu, A.S.Y.; Yelekçi, K.; Ibrahim Uba, A. The design of potent HIV-1 integrase inhibitors by a combined approach of structure-based virtual screening and molecular dynamics simulation. J. Biomol. Struct. Dyn., 2019, 37(17), 4644-4650.
[http://dx.doi.org/10.1080/07391102.2018.1557559] [PMID: 30526403]
[27]
Vora, J.; Patel, S.; Sinha, S.; Sharma, S.; Srivastava, A.; Chhabria, M.; Shrivastava, N. Molecular docking, qsar and admet based mining of natural compounds against prime targets of HIV. J. Biomol. Struct. Dyn., 2019, 37(1), 131-146.
[http://dx.doi.org/10.1080/07391102.2017.1420489] [PMID: 29268664]
[28]
Sirous, H.; Chemi, G.; Gemma, S.; Butini, S.; Debyser, Z.; Christ, F.; Saghaie, L.; Brogi, S.; Fassihi, A.; Campiani, G.; Brindisi, M. Identification of novel 3-Hydroxy-pyran-4-one derivatives as potent HIV-1 integrase inhibitors using in silico structure-based combinatorial library design approach. Front Chem., 2019, 7, 574.
[http://dx.doi.org/10.3389/fchem.2019.00574] [PMID: 31457006]
[29]
Eurtivong, C.; Choowongkomon, K.; Ploypradith, P.; Ruchirawat, S. Molecular docking study of lamellarin analogues and identification of potential inhibitors of HIV-1 integrase strand transfer complex by virtual screening. Heliyon, 2019, 5(11), e02811.
[http://dx.doi.org/10.1016/j.heliyon.2019.e02811] [PMID: 31763475]
[30]
Patel, S.B.P.; Patel, B.D.; Pannecouque, C.; Bhatt, H.G. Design, synthesis and anti-HIV activity of novel quinoxaline derivatives. Eur. J. Med. Chem., 2016, 117, 230-240.
[http://dx.doi.org/10.1016/j.ejmech.2016.04.019] [PMID: 27105027]
[31]
Guasch, L.; Zakharov, A.V.; Tarasova, O.A.; Poroikov, V.V.; Liao, C.; Nicklaus, M.C. Novel HIV-1 integrase inhibitor development by virtual screening based on qsar models. Curr. Top. Med. Chem., 2016, 16(4), 441-448.
[http://dx.doi.org/10.2174/1568026615666150813150433] [PMID: 26268340]
[32]
Islam, M.A.P.; Pillay, T.S. Structural requirements for potential HIV-integrase inhibitors identified using pharmacophore-based virtual screening and molecular dynamics studies. Mol. Biosyst., 2016, 12(3), 982-993.
[http://dx.doi.org/10.1039/C5MB00767D] [PMID: 26809073]
[33]
Poongavanam, V.; Corona, A.; Steinmann, C.; Scipione, L.; Grandi, N.; Pandolfi, F.; Di Santo, R.; Costi, R.; Esposito, F.; Tramontano, E.; Kongsted, J. Structure-guided approach identifies a novel class of HIV-1 ribonuclease H inhibitors: Binding mode insights through magnesium complexation and site-directed mutagenesis studies. MedChemComm, 2018, 9(3), 562-575.
[http://dx.doi.org/10.1039/C7MD00600D] [PMID: 30108947]
[34]
Xue, W.; Liu, H.; Yao, X. Molecular mechanism of HIV-1 integrase-vDNA interactions and strand transfer inhibitor action: A molecular modeling perspective. J. Comput. Chem., 2012, 33(5), 527-536.
[http://dx.doi.org/10.1002/jcc.22887] [PMID: 22144113]
[35]
Xue, W.; Jin, X.; Ning, L.; Wang, M.; Liu, H.; Yao, X. Exploring the molecular mechanism of cross-resistance to HIV-1 integrase strand transfer inhibitors by molecular dynamics simulation and residue interaction network analysis. J. Chem. Inf. Model., 2013, 53(1), 210-222.
[http://dx.doi.org/10.1021/ci300541c] [PMID: 23231029]
[36]
Chander, S.; Pandey, R.K.; Penta, A.; Choudhary, B.S.; Sharma, M.; Malik, R.; Prajapati, V.K.; Murugesan, S. Molecular docking and molecular dynamics simulation based approach to explore the dual inhibitor against HIV-1 reverse transcriptase and integrase. Comb. Chem. High Throughput Screen., 2017, 20(8), 734-746.
[http://dx.doi.org/10.2174/1386207320666170615104703] [PMID: 28641512]
[37]
Chen, Q.; Cheng, X.; Wei, D.; Xu, Q. Molecular dynamics simulation studies of the wild type and E92Q/N155H mutant of Elvitegravir-resistance HIV-1 integrase. Interdiscip. Sci., 2015, 7(1), 36-42.
[PMID: 25519157]
[38]
Hare, S.; Gupta, S.S.; Valkov, E.; Engelman, A.; Cherepanov, P. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature, 2010, 464(7286), 232-236.
[http://dx.doi.org/10.1038/nature08784] [PMID: 20118915]
[39]
Chitongo, R.; Obasa, A.E.; Mikasi, S.G.; Jacobs, G.B.; Cloete, R. Molecular dynamic simulations to investigate the structural impact of known drug resistance mutations on HIV-1C Integrase-dolutegravir binding. PLoS One, 2020, 15(5), e0223464.
[http://dx.doi.org/10.1371/journal.pone.0223464] [PMID: 32379830]
[40]
Malet, I.; Ambrosio, F.A.; Subra, F.; Herrmann, B.; Leh, H.; Bouger, M.C.; Artese, A.; Katlama, C.; Talarico, C.; Romeo, I.; Alcaro, S.; Costa, G.; Deprez, E.; Calvez, V.; Marcelin, A.G.; Delelis, O. Pathway involving the N155H mutation in HIV-1 integrase leads to dolutegravir resistance. J. Antimicrob. Chemother., 2018, 73(5), 1158-1166.
[http://dx.doi.org/10.1093/jac/dkx529] [PMID: 29373677]
[41]
Riemenschneider, M.; Heider, D. Current approaches in computational drug resistance prediction in HIV. Curr. HIV Res., 2016, 14(4), 307-315.
[http://dx.doi.org/10.2174/1570162X14666160321120232] [PMID: 26996942 ]
[42]
Schmidt, B.; Walter, H.; Moschik, B.; Paatz, C.; van Vaerenbergh, K.; Vandamme, A.M.; Schmitt, M.; Harrer, T.; Uberla, K.; Korn, K. Simple algorithm derived from a geno-/phenotypic database to predict HIV-1 protease inhibitor resistance. AIDS, 2000, 14(12), 1731-1738.
[http://dx.doi.org/10.1097/00002030-200008180-00007] [PMID: 10985309]
[43]
Bonet, I. Machine Learning for Prediction of HIV Drug Resistance: A Review. Curr. Bioinform., 2015, (10), 579-585.
[http://dx.doi.org/10.2174/1574893610666151008011731]
[44]
Masso, M. Sequence-based predictive models of resistance to HIV-1 integrase inhibitors: An n-grams approach to phenotype assessment. Curr. HIV Res., 2015, 13(6), 497-502.
[http://dx.doi.org/10.2174/1570162X13666150624100535] [PMID: 26105155 ]
[45]
Ramon, E.; Belanche-Muñoz, L.; Pérez-Enciso, M. HIV drug resistance prediction with weighted categorical kernel functions. BMC Bioinformatics, 2019, 20(1), 410.
[http://dx.doi.org/10.1186/s12859-019-2991-2] [PMID: 31362714]
[46]
Sachithanandham, J.; Konda Reddy, K.; Solomon, K.; David, S.; Kumar Singh, S.; Vadhini Ramalingam, V.; Alexander Pulimood, S.; Cherian Abraham, O.; Rupali, P.; Sridharan, G.; Kannangai, R. Effect of HIV-1 Subtype C integrase mutations implied using molecular modeling and docking data. Bioinformation, 2016, 12(3), 221-230.
[http://dx.doi.org/10.6026/97320630012221] [PMID: 28149058]
[47]
da Silva, H.H.S.A.; Pereira, N.; Brandão, L.; Crovella, S.; Moura, R. Prediction of HIV integrase resistance mutation using in silico approaches. Infect. Genet. Evol., 2019, 68, 10-15.
[http://dx.doi.org/10.1016/j.meegid.2018.11.014] [PMID: 30453083]
[48]
Passos, D.O.L.; 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]
[49]
Sohn, Y.S.P.; Park, C.; Lee, Y.; Kim, S.; Thangapandian, S.; Kim, Y.; Kim, H.H.; Suh, J.K.; Lee, K.W. Multi-conformation dynamic pharmacophore modeling of the peroxisome proliferator-activated receptor γ for the discovery of novel agonists. J. Mol. Graph. Model., 2013, 46, 1-9.
[http://dx.doi.org/10.1016/j.jmgm.2013.08.012] [PMID: 24104184]
[50]
Copeland, R.A.P.; Pompliano, D.L.; Meek, T.D. Drug-target residence time and its implications for lead optimization. Nat. Rev. Drug Discov., 2006, 5(9), 730-739.
[http://dx.doi.org/10.1038/nrd2082] [PMID: 16888652 ]
[51]
Hightower, K.E.W.; Wang, R.; Deanda, F.; Johns, B.A.; Weaver, K.; Shen, Y.; Tomberlin, G.H.; Carter, H.L., III; Broderick, T.; Sigethy, S.; Seki, T.; Kobayashi, M.; Underwood, M.R. Dolutegravir (S/GSK1349572) exhibits significantly slower dissociation than raltegravir and elvitegravir from wild-type and integrase inhibitor-resistant HIV-1 integrase-DNA complexes. Antimicrob. Agents Chemother., 2011, 55(10), 4552-4559.
[http://dx.doi.org/10.1128/AAC.00157-11] [PMID: 21807982 ]
[52]
Garvey, E.P.S.; Schwartz, B.; Gartland, M.J.; Lang, S.; Halsey, W.; Sathe, G.; Carter, H.L., III; Weaver, K.L. Potent inhibitors of HIV-1 integrase display a two-step, slow-binding inhibition mechanism which is absent in a drug-resistant T66I/M154I mutant. Biochemistry, 2009, 48(7), 1644-1653.
[http://dx.doi.org/10.1021/bi802141y] [PMID: 19178153]

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