Login Register Cart 0
Generic placeholder image

Current Computer-Aided Drug Design

Editor-in-Chief

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

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Quantitative Structure-Activity Relationship Study for HIV-1 LEDGF/p75 Inhibitors

Author(s): Yang Li, Yujia Tian, Yao Xi, Zijian Qin and Aixia Yan*

Volume 16, Issue 5, 2020

Page: [654 - 666] Pages: 13

DOI: 10.2174/1573409915666190919153959

Price: $65

conference banner
Abstract

Background: HIV-1 Integrase (IN) is an important target for the development of the new anti-AIDS drugs. HIV-1 LEDGF/p75 inhibitors, which block the integrase and LEDGF/p75 interaction, have been validated for reduction in HIV-1 viral replicative capacity.

Methods: In this work, computational Quantitative Structure-Activity Relationship (QSAR) models were developed for predicting the bioactivity of HIV-1 integrase LEDGF/p75 inhibitors. We collected 190 inhibitors and their bioactivities in this study and divided the inhibitors into nine scaffolds by the method of T-distributed Stochastic Neighbor Embedding (TSNE). These 190 inhibitors were split into a training set and a test set according to the result of a Kohonen’s self-organizing map (SOM) or randomly. Multiple Linear Regression (MLR) models, support vector machine (SVM) models and two consensus models were built based on the training sets by 20 selected CORINA Symphony descriptors.

Results: All the models showed a good prediction of pIC50. The correlation coefficients of all the models were more than 0.7 on the test set. For the training set of consensus Model C1, which performed better than other models, the correlation coefficient(r) achieved 0.909 on the training set, and 0.804 on the test set.

Conclusion: The selected molecular descriptors show that hydrogen bond acceptor, atom charges and electronegativities (especially π atom) were important in predicting the activity of HIV-1 integrase LEDGF/p75-IN inhibitors.

Keywords: HIV-1 integrase, LEDGF/p75 inhibitor, chemical scaffold, quantitative structure-activity relationship (QSAR) model, molecular descriptor.

« Previous
Graphical Abstract

[1]
The United Nations Programme on HIV/AIDS Tremendous progress against AIDS over the past 15 years has inspired a global commitment to end the epidemic by 2030 [EB/OL]., http://www.unaids.org/
[2]
Hajimahdi, Z.; Zarghi, A. Progress in HIV-1 integrase inhibitors: a review of their chemical structure diversity. Iran. J. Pharm. Res., 2016, 15(4), 595-628.
[PMID: 28243261]
[3]
Blanco, J.L.; Whitlock, G.; Milinkovic, A.; Moyle, G. HIV integrase inhibitors: a new era in the treatment of HIV. Expert Opin. Pharmacother., 2015, 16(9), 1313-1324.
[http://dx.doi.org/10.1517/14656566.2015.1044436] [PMID: 26001181]
[4]
Li, Y.; Xuan, S.; Feng, Y.; Yan, A. Targeting HIV-1 integrase with strand transfer inhibitors. Drug Discov. Today, 2015, 20(4), 435-449.
[http://dx.doi.org/10.1016/j.drudis.2014.12.001] [PMID: 25486307]
[5]
Cherepanov, P.; Maertens, G.; Proost, P.; Devreese, B.; Van Beeumen, J.; Engelborghs, Y.; De Clercq, E.; Debyser, Z. HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells. J. Biol. Chem., 2003, 278(1), 372-381.
[http://dx.doi.org/10.1074/jbc.M209278200] [PMID: 12407101]
[6]
Ward, C.J. Novel drugs and treatment strategies for HIV-1. Expert Rev. Anti Infect. Ther., 2012, 10(11), 1265-1267.
[http://dx.doi.org/10.1586/eri.12.119] [PMID: 23241181]
[7]
Barril, X. Computer-aided drug design: time to play with novel chemical matter. Expert Opin. Drug Discov., 2017, 12(10), 977-980.
[http://dx.doi.org/10.1080/17460441.2017.1362386] [PMID: 28756685]
[8]
Cherkasov, A.; Muratov, E.N.; Fourches, D.; Varnek, A.; Baskin, I.I.; Cronin, M.; Dearden, J.; Gramatica, P.; Martin, Y.C.; Todeschini, R.; Consonni, V.; Kuz’min, V.E.; Cramer, R.; Benigni, R.; Yang, C.; Rathman, J.; Terfloth, L.; Gasteiger, J.; Richard, A.; Tropsha, A. QSAR modeling: where have you been? Where are you going to? J. Med. Chem., 2014, 57(12), 4977-5010.
[http://dx.doi.org/10.1021/jm4004285] [PMID: 24351051]
[9]
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]
[10]
Iyer, M.; Hopfinger, A.J. Treating chemical diversity in QSAR analysis: modeling diverse HIV-1 integrase inhibitors using 4D fingerprints. J. Chem. Inf. Model., 2007, 47(5), 1945-1960.
[http://dx.doi.org/10.1021/ci700153g] [PMID: 17661457]
[11]
Yuan, H.; Parrill, A.L. QSAR studies of HIV-1 integrase inhibition. Bioorg. Med. Chem., 2002, 10(12), 4169-4183.
[http://dx.doi.org/10.1016/S0968-0896(02)00332-2] [PMID: 12413870]
[12]
Xuan, S.; Wu, Y.; Chen, X.; Liu, J.; Yan, A. Prediction of bioactivity of HIV-1 integrase ST inhibitors by multilinear regression analysis and support vector machine. Bioorg. Med. Chem. Lett., 2013, 23(6), 1648-1655.
[http://dx.doi.org/10.1016/j.bmcl.2013.01.081] [PMID: 23395655]
[13]
Yan, A.; Xuan, S.; Hu, X. Classification of active and weakly active ST inhibitors of HIV-1 integrase using a support vector machine. Comb. Chem. High Throughput Screen., 2012, 15(10), 792-805.
[http://dx.doi.org/10.2174/138620712803901108] [PMID: 22934952]
[14]
Kong, Y.; Xuan, S.; Yan, A. Computational models on quantitative prediction of bioactivity of HIV-1 integrase 3′ processing inhibitors. SAR QSAR Environ. Res., 2014, 25(9), 729-746.
[http://dx.doi.org/10.1080/1062936X.2014.942695] [PMID: 25121566]
[15]
Xuan, S.; Wang, M.; Kang, H.; Kirchmair, J.; Tan, L.; Yan, A. Support Vector Machine (SVM) Models for Predicting Inhibitors of the 3′ Processing Step of HIV-1 Integrase. Mol. Inform., 2013, 32(9-10), 811-826.
[http://dx.doi.org/10.1002/minf.201300107] [PMID: 27480234]
[16]
Li, Y.; Wu, Y.; Yan, A. Study of structure-active relationship for inhibitors of HIV-1 Integrase LEDGF/p75 interaction by machine learning methods. Mol. Inform., 2017, 36(7)1600127
[http://dx.doi.org/10.1002/minf.201600127] [PMID: 28244220]
[17]
Cuzzucoli Crucitti, G.; Pescatori, L.; Messore, A.; Madia, V.N.; Pupo, G.; Saccoliti, F.; Scipione, L.; Tortorella, S.; Di Leva, F.S.; Cosconati, S.; Novellino, E.; Debyser, Z.; Christ, F.; Costi, R.; Di Santo, R. Discovery of N-aryl-naphthylamines as in vitro inhibitors of the interaction between HIV integrase and the cofactor LEDGF/p75. Eur. J. Med. Chem., 2015, 101, 288-294.
[http://dx.doi.org/10.1016/j.ejmech.2015.06.036] [PMID: 26150289]
[18]
De Luca, L.; Ferro, S.; Gitto, R.; Barreca, M.L.; Agnello, S.; Christ, F.; Debyser, Z.; Chimirri, A. Small molecules targeting the interaction between HIV-1 integrase and LEDGF/p75 cofactor. Bioorg. Med. Chem., 2010, 18(21), 7515-7521.
[http://dx.doi.org/10.1016/j.bmc.2010.08.051] [PMID: 20850978]
[19]
De Luca, L.; Morreale, F.; Christ, F.; Debyser, Z.; Ferro, S.; Gitto, R. New scaffolds of natural origin as Integrase-LEDGF/p75 interaction inhibitors: virtual screening and activity assays. Eur. J. Med. Chem., 2013, 68, 405-411.
[http://dx.doi.org/10.1016/j.ejmech.2013.07.025] [PMID: 23994868]
[20]
Fan, X.; Zhang, F.H.; Al-Safi, R.I.; Zeng, L.F.; Shabaik, Y.; Debnath, B.; Sanchez, T.W.; Odde, S.; Neamati, N.; Long, Y.Q. Design of HIV-1 integrase inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75: a scaffold hopping approach using salicylate and catechol groups. Bioorg. Med. Chem., 2011, 19(16), 4935-4952.
[http://dx.doi.org/10.1016/j.bmc.2011.06.058] [PMID: 21778063]
[21]
Feng, L.; Sharma, A.; Slaughter, A.; Jena, N.; Koh, Y.; Shkriabai, N.; Larue, R.C.; Patel, P.A.; Mitsuya, H.; Kessl, J.J.; Engelman, A.; Fuchs, J.R.; Kvaratskhelia, M. The A128T resistance mutation reveals aberrant protein multimerization as the primary mechanism of action of allosteric HIV-1 integrase inhibitors. J. Biol. Chem., 2013, 288(22), 15813-15820.
[http://dx.doi.org/10.1074/jbc.M112.443390] [PMID: 23615903]
[22]
Ferro, S.; De Luca, L.; Lo Surdo, G.; Morreale, F.; Christ, F.; Debyser, Z.; Gitto, R.; Chimirri, A. A new potential approach to block HIV-1 replication via protein-protein interaction and strand-transfer inhibition. Bioorg. Med. Chem., 2014, 22(7), 2269-2279.
[http://dx.doi.org/10.1016/j.bmc.2014.02.012] [PMID: 24618511]
[23]
Ferro, S.; De Luca, L.; Morreale, F.; Christ, F.; Debyser, Z.; Gitto, R.; Chimirri, A. Synthesis and biological evaluation of novel antiviral agents as protein-protein interaction inhibitors. J. Enzyme Inhib. Med. Chem., 2014, 29(2), 237-242.
[http://dx.doi.org/10.3109/14756366.2013.766609] [PMID: 23859152]
[24]
Hu, G.; Li, X.; Li, Y.; Sun, X.; Liu, G.; Li, W.; Huang, J.; Shen, X.; Tang, Y. Inhibitors of HIV-1 integrase-Human LEDGF/p75 interaction identified from natural products via virtual screening. Chin. J. Chem., 2012, 30, 2752-2758.
[http://dx.doi.org/10.1002/cjoc.201200897]
[25]
Harrison, A.T.; Kriel, F.H.; Papathanasopoulos, M.A.; Mosebi, S.; Abrahams, S.; Hewer, R. The evaluation of statins as potential inhibitors of the LEDGF/p75-HIV-1 integrase interaction. Chem. Biol. Drug Des., 2015, 85(3), 290-295.
[http://dx.doi.org/10.1111/cbdd.12384] [PMID: 24954548]
[26]
Hu, G.; Li, X.; Sun, X.; Lu, W.; Liu, G.; Huang, J.; Shen, X.; Tang, Y. Identification of old drugs as potential inhibitors of HIV-1 integrase - human LEDGF/p75 interaction via molecular docking. J. Mol. Model., 2012, 18(12), 4995-5003.
[http://dx.doi.org/10.1007/s00894-012-1494-0] [PMID: 22733274]
[27]
Hu, G.; Li, X.; Zhang, X.; Li, Y.; Ma, L.; Yang, L.M.; Liu, G.; Li, W.; Huang, J.; Shen, X.; Hu, L.; Zheng, Y.T.; Tang, Y. Discovery of inhibitors to block interactions of HIV-1 integrase with human LEDGF/p75 via structure-based virtual screening and bioassays. J. Med. Chem., 2012, 55(22), 10108-10117.
[http://dx.doi.org/10.1021/jm301226a] [PMID: 23046280]
[28]
Kessl, J.J.; Jena, N.; Koh, Y.; Taskent-Sezgin, H.; Slaughter, A.; Feng, L.; de Silva, S.; Wu, L.; Le Grice, S.F.; Engelman, A.; Fuchs, J.R.; Kvaratskhelia, M. Multimode, cooperative mechanism of action of allosteric HIV-1 integrase inhibitors. J. Biol. Chem., 2012, 287(20), 16801-16811.
[http://dx.doi.org/10.1074/jbc.M112.354373] [PMID: 22437836]
[29]
Li, B.W.; Zhang, F.H.; Serrao, E.; Chen, H.; Sanchez, T.W.; Yang, L.M.; Neamati, N.; Zheng, Y.T.; Wang, H.; Long, Y.Q. Design and discovery of flavonoid-based HIV-1 integrase inhibitors targeting both the active site and the interaction with LEDGF/p75. Bioorg. Med. Chem., 2014, 22(12), 3146-3158.
[http://dx.doi.org/10.1016/j.bmc.2014.04.016] [PMID: 24794743]
[30]
Long, Y.Q.; Huang, S.X.; Zawahir, Z.; Xu, Z.L.; Li, H.; Sanchez, T.W.; Zhi, Y.; De Houwer, S.; Christ, F.; Debyser, Z.; Neamati, N. Design of cell-permeable stapled peptides as HIV-1 integrase inhibitors. J. Med. Chem., 2013, 56(13), 5601-5612.
[http://dx.doi.org/10.1021/jm4006516] [PMID: 23758584]
[31]
Sanchez, T.W.; Debnath, B.; Christ, F.; Otake, H.; Debyser, Z.; Neamati, N. Discovery of novel inhibitors of LEDGF/p75-IN protein-protein interactions. Bioorg. Med. Chem., 2013, 21(4), 957-963.
[http://dx.doi.org/10.1016/j.bmc.2012.12.012] [PMID: 23306052]
[32]
Serrao, E.; Debnath, B.; Otake, H.; Kuang, Y.; Christ, F.; Debyser, Z.; Neamati, N. Fragment-based discovery of 8-hydroxyquinoline inhibitors of the HIV-1 integrase-lens epithelium-derived growth factor/p75 (IN-LEDGF/p75) interaction. J. Med. Chem., 2013, 56(6), 2311-2322.
[http://dx.doi.org/10.1021/jm301632e] [PMID: 23445471]
[33]
Serrao, E.; Xu, Z.L.; Debnath, B.; Christ, F.; Debyser, Z.; Long, Y.Q.; Neamati, N. Discovery of a novel 5-carbonyl-1H-imidazole-4-carboxamide class of inhibitors of the HIV-1 integrase-LEDGF/p75 interaction. Bioorg. Med. Chem., 2013, 21(19), 5963-5972.
[http://dx.doi.org/10.1016/j.bmc.2013.07.047] [PMID: 23985689]
[34]
Yu, F.; Jones, G.S.; Hung, M.; Wagner, A.H.; MacArthur, H.L.; Liu, X.; Leavitt, S.; McDermott, M.J.; Tsiang, M. HIV-1 integrase preassembled on donor DNA is refractory to activity stimulation by LEDGF/p75. Biochemistry, 2007, 46(10), 2899-2908.
[http://dx.doi.org/10.1021/bi602387u] [PMID: 17298035]
[35]
Zhang, F.H.; Debnath, B.; Xu, Z.L.; Yang, L.M.; Song, L.R.; Zheng, Y.T.; Neamati, N.; Long, Y.Q. Discovery of novel 3-hydroxypicolinamides as selective inhibitors of HIV-1 integrase-LEDGF/p75 interaction. Eur. J. Med. Chem., 2017, 125, 1051-1063.
[http://dx.doi.org/10.1016/j.ejmech.2016.10.045] [PMID: 27810592]
[36]
Ribone, S.R.; Quevedo, M.A. Structural basis for the potent inhibition of the HIV integrase-LEDGF/p75 protein-protein interaction. J. Mol. Graph. Model., 2017, 75, 189-198.
[http://dx.doi.org/10.1016/j.jmgm.2017.05.019] [PMID: 28582696]
[37]
Zhao, Y.; Luo, Z. Recent advances in the development of small-molecular inhibitors target HIV Integrase-LEDGF/p75 interaction. Mini Rev. Med. Chem., 2015, 15(14), 1195-1208.
[http://dx.doi.org/10.2174/1389557515666150709114917] [PMID: 26156421]
[38]
Symphony, C.O.R.I.N.A.; Molecular Networks Gmb, H. www.molecular-networks.com2016.
[39]
Ullman, E.F.; Kirakossian, H.; Singh, S.; Wu, Z.P.; Irvin, B.R.; Pease, J.S.; Switchenko, A.C.; Irvine, J.D.; Dafforn, A.; Skold, C.N. Luminescent oxygen channeling immunoassay: measurement of particle binding kinetics by chemiluminescence. Proc. Natl. Acad. Sci. USA, 1994, 91(12), 5426-5430.
[http://dx.doi.org/10.1073/pnas.91.12.5426] [PMID: 8202502]
[40]
Yasgar, A.; Jadhav, A.; Simeonov, A.; Coussens, N.P. AlphaScreen-Based assays: ultra-high-throughput screening for small-molecule inhibitors of challenging enzymes and protein-protein interactions. Methods Mol. Biol., 2016, 1439, 77-98.
[http://dx.doi.org/10.1007/978-1-4939-3673-1_5] [PMID: 27316989]
[41]
Van der Maaten, L.J.P.; Hinton, G.E. Visualizing data using t-SNE. J. Mach. Learn. Res., 2008, 9, 2579-2605.
[42]
Rogers, D.; Hahn, M. Extended-connectivity fingerprints. J. Chem. Inf. Model., 2010, 50(5), 742-754.
[http://dx.doi.org/10.1021/ci100050t] [PMID: 20426451]
[43]
Kohonen, T. Self-organized formation of topologically correct feature maps. Biol. Cybern., 1982, 43, 59-69.
[http://dx.doi.org/10.1007/BF00337288]
[44]
Keys, MACCS
[45]
Veber, D.F.; Johnson, S.R.; Cheng, H.Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem., 2002, 45(12), 2615-2623.
[http://dx.doi.org/10.1021/jm020017n] [PMID: 12036371]
[46]
Bauknecht, H.; Zell, A.; Bayer, H.; Levi, P.; Wagener, M.; Sadowski, J.; Gasteiger, J. Locating biologically active compounds in medium-sized heterogeneous datasets by topological autocorrelation vectors: dopamine and benzodiazepine agonists. J. Chem. Inf. Comput. Sci., 1996, 36(6), 1205-1213.
[http://dx.doi.org/10.1021/ci960346m] [PMID: 8941996]
[47]
Fernández Pierna, J.A.; Abbas, O.; Baeten, V.; Dardenne, P. A Backward Variable Selection method for PLS regression (BVSPLS). Anal. Chim. Acta, 2009, 642(1-2), 89-93.
[http://dx.doi.org/10.1016/j.aca.2008.12.002] [PMID: 19427462]
[48]
Liu, R.; Wang, H.; Glover, K.P.; Feasel, M.G.; Wallqvist, A. Dissecting machine-learning prediction of molecular activity: is an applicability domain needed for quantitative structure-activity relationship models based on deep neural networks? J. Chem. Inf. Model., 2019, 59(1), 117-126.
[http://dx.doi.org/10.1021/acs.jcim.8b00348] [PMID: 30412667]
[49]
Heikamp, K.; Bajorath, J. Support vector machines for drug discovery. Expert Opin. Drug Discov., 2014, 9(1), 93-104.
[http://dx.doi.org/10.1517/17460441.2014.866943] [PMID: 24304044]
[50]
Nizami, B.; Tetko, I.V.; Koorbanally, N.A.; Honarparvar, B. QSAR models and scaffold-based analysis of non-nucleoside HIV RT inhibitors. Chemometr. Intell. Lab., 2015, 148, 134-144.
[http://dx.doi.org/10.1016/j.chemolab.2015.09.011]
[51]
Kuz’min, E.V.; Muratov, N. E.; G.Artemeko. A.; V.Varlamova. E.; Gorb. L.; Wang. J.; Leszczynski J. Consensus QSAR modeling of phosphor-containing chiral ache inhibitors. QSAR Comb. Sci., 2009, 6-7, 664-677.
[http://dx.doi.org/10.1002/qsar.200860117]
[52]
Peat, T.S.; Rhodes, D.I.; Vandegraaff, N.; Le, G.; Smith, J.A.; Clark, L.J.; Jones, E.D.; Coates, J.A.; Thienthong, N.; Newman, J.; Dolezal, O.; Mulder, R.; Ryan, J.H.; Savage, G.P.; Francis, C.L.; Deadman, J.J. Small molecule inhibitors of the LEDGF site of human immunodeficiency virus integrase identified by fragment screening and structure based design. PLoS One, 2012, 7(7)e40147
[http://dx.doi.org/10.1371/journal.pone.0040147] [PMID: 22808106]
[53]
Christ, F.; Shaw, S.; Demeulemeester, J.; Desimmie, B.A.; Marchand, A.; Butler, S.; Smets, W.; Chaltin, P.; Westby, M.; Debyser, Z.; Pickford, C. Small-molecule inhibitors of the LEDGF/p75 binding site of integrase block HIV replication and modulate integrase multimerization. Antimicrob. Agents Chemother., 2012, 56(8), 4365-4374.
[http://dx.doi.org/10.1128/AAC.00717-12] [PMID: 22664975]

Rights & Permissions Print Cite
Article Metrics
14
© 2024 Bentham Science Publishers | Privacy Policy