QSAR and Docking Studies of DATA Analogues as HIV-1 Reverse Transcriptase Inhibitors

Author(s): Jianbo Tong*, Shan Lei, Pei Zhan, Shangshang Qin, Yang Wang

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 2 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Acquired Immunodeficiency Syndrome (AIDS) caused by Human Immunodeficiency Virus (HIV) has seriously threatened human health, so development of new, selective and safe non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) remains a high priority for medical research. Diaryltriazine (DATA) have been identified as a new class of potent nonnucleoside HIV-1 Reverse Transcriptase (RT) inhibitors. The study deals with Topomer CoMFA (Comparative Molecular Field Analysis) and molecular docking to explore the important features of DATA analogues for exerting potent HIV-1 RT inhibitors activity.

Methods: In this work, 40 DATA analogues were studied using a combination of molecular modeling techniques including Three-Dimensional Quantitative Structure–Activity Relationship (3D-QSAR), molecular docking, and Topomer CoMFA were used to build 3D-QSAR models.

Results: The results show that the Topomer CoMFA analysis has the cross-validation q2 = 0.800, SDCV = 0.45, the non-cross-validated r2 = 0.958, SD = 0.21, and the correlation coefficient of external validation Q2 ext = 0.965 showed that the model is reasonable and credible, and has a good predictive ability. Then binding mode pattern of the compounds to the binding site of enzyme was confirmed and the mechanism of drug and acceptor was studied by docking studies, the results showed that the drug and GLU138, LYS101, THR139 sites have an obvious function, these researches have provided an useful information for designing more effective HIV-1IN inhibitors.

Conclusion: A series of 40 DATAs analogues was subjected to a 3D-QSAR study. Using Topomer CoMFA 3D-QSAR method built model, and the model has shown a good predictive and statistical validation. Substituent with low electronic density in the R5 and R3 positions and substituent with high electronic density in the R2 and C2 positions will increase the biological activity, small substituent on R4 positions and naphthyloxy as the spacer group C6 substituent hydrophobic will increase biological activity. This effect is supported by Topomer CoMFA contour map and docking results of HIV-1RT inhibition active site, the results of the 3D-QSAR and docking analyses have provided a guide for the synthesis of new putative inhibitors for HIV-1RT to improved inhibitory activity.

Keywords: 3D-QSAR, diaryltriazines, topomer CoMFA, molecular docking, electronic density, DATA.

[1]
Marx, J.L. New disease baffles medical community. Science, 1982, 217, 618-621.
[2]
Barin, F.; M'Boup, S.; Denis, F.; Kanki, P.; Allan, J.S.; Lee, T.H.; Essex, M. Serological evidence for virus related to simian T-lymphotropic retrovirus III in residents of West Africa.Lancet, 1985, 2(8469-70): 1387-1389,
[3]
Xian Xing, X Study on Genetic Stability Biodistribution and Humunity of Ad5/35-HEGC/MVA-HGEC for AIDS Treatment Vaccine [D]. Academy of Military Medical Science, Chinese People’s Liberation Army, 2011,
[4]
Reeves, J.D.; Doms, R.W. Human immunodeficiency virus type 2. J. Gen. Virol., 2002, 83, 1253-1265.
[5]
Artico, M. Non-nucleoside anti-HIV-1 reverse transcriptase inhibitors (NNRTIs): A chemical survey from lead compounds to selected drugs for clinical trials. ChemInform, 1996, 27, 6195-6200.
[6]
Martin, J.A.; Redshaw, S.; Thomas, G.J. Inhibitors of HIV proteinase. Prog. Med. Chem., 1995, 32, 239-287.
[7]
Barreca, M.L.; Ferro, S.; Rao, A.; Luca, L.D.; Zappala, M.; Monforte, A.M.; Debyser, Z.; Witvrouw, M.; Chimirri, A. Pharmacophore-based design of HIV-1 integrase strand-transfer inhibitors. J. Med. Chem., 2005, 48, 7084-7088.
[8]
D’Angelo, J.; Mouscadet, J.F.; Desmaele, F.; Zouhiri, F.; Leh, H. HIV-1 integrase: The next target for AIDS therapy. Pathol. Biol. , 2001, 49, 237-246.
[9]
He, Y.; Chen, F.; Sun, G.; Wang, Y.; Clercq, E.De Balzarini, J.; Pannecouque, C. 5-Alkyl-2-[(aryl and alkyloxylcarbonylmethyl) thio]-6-(1-naphthylmethyl)pyrimidin-4(3H)-ones as an unique HIV reverse transcriptase inhibitors of S-DABO series. Bioorg. Med. Chem. Lett., 2004, 14, 3173-3176.
[10]
Monforte, A.M.; Logoteta, P.; De Luca, L.; Iraci, N.; Ferro, S.; Maga, G.; De Clercq, E.; Pannecouque, C.; Chimirri, A. Novel 1, 3-dihydro-benzimidazol-2-ones and their analogues as potent non-nucleoside HIV-1 reverse transcriptase inhibitors. Bioorg. Med. Chem., 2010, 18, 1702-1710.
[11]
Ludovici, D.W.; Kavash, R.W.; Kukla, M.J.; Ho, C.Y.; Ye, H.; De Corte, B.L.; Andries, K.; de Béthune, M.P.; Azijn, H.; Pauwels, R.; Moereels, H.E.; Heeres, J.; Koymans, L.M.; de Jonge, M.R.; Van Aken, K.J.; Daeyaert, F.F.; Lewi, P.J.; Das, K.; Arnold, E.; Janssen, P.A. Evolution of anti-HIV drug candidates. Part 2: Diaryltriazine (DATA) analogues. Bioorg. Med. Chem. Lett., 2001, 11(17), 2229-2234.
[12]
Bhadoriya, K.S.; Jain, S.V.; Bari, S.B.; Chavhan, M.L.; Vispute, K.R. 3D-QSAR study of indol-2-yl ethanones derivatives as novelindoleamine 2, 3-dioxygenase (IDO) inhibitors. J. Med. Chem., 2012, 9, 1753-1759.
[13]
Jain, S.V.; Ghate, M.; Bhadoriya, K.S.; Bari, S.B.; Chaudhari, A.; Borse, J.S. 2D 3D-QSAR and docking studies of 1, 2, 3-thiadiazolethioacetanilides analogues as potent HIV-1 non-nucleoside reverse transcriptase inhibitors. Org. Med. Chem. Lett., 2012, 2, 2-13.
[14]
Clark, M.; Iii, R.D.C.; Opdenbosch, N.V. Validation of the general purpose tripos 5.2 force field. J. Comput. Chem., 1989, 10(8), 982-1012.
[15]
Gasteiger, J.; Marsili, M. Iterative partial equalization of orbital electronegativity-a rapid access to atomic charges. Tetrahedron, 1980, 36(22), 3219-3228.
[16]
Liu, Y.X.; Shi, H.F. Study on three-dimensional quantitative structure-activity relationship of curcuminoids based on topomer CoMFA method. J. Technol. Develop. Chem. Industry, 2014, 43, 36-38.
[17]
Wang, Q.; Mei, H.; Sun, J.Y.; Lin, Z. Molecular docking and 3d-qsar research of diaryltriazines derivatives as HIV-1 reverse transcriptase inhibitors. Chemistry, 2011, 29(1), 54-60.
[18]
Gangjee, A.; Adair, O.; Queener, S.F. Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase inhibitors and antitumor agents: Synthesis and biological activities of 2,4-diamino-5-methyl-6-[(monosubstituted anilino) methyl] pyrido[2,3-d]pyrimidines. J. Med. Chem., 1999, 42, 2447-2455.
[19]
Yue, J.; Shi, L.; Xie, Z.; Xing, Y.; Jing, X. Size-dependent biodistribution and antitumor efficacy of polymer micelle drug delivery systems. J. Mater. Chem., 2013, 2013, 4273-4280.
[20]
Gangjee, A.; Vidwans, A.P.; Vasudevan, A.; Queener, S.F.; Kisliuk, R.L.; Cody, V.; Li, R.M.; Galitsky, N.; Luft, J.R.; Pangborn, S. Structure based design and synthesis of lipophilic 2,4-diamino-6-substituted quinazolines and their evaluation as inhibitors of dihydrofolate reductases and potential antitumor agents. J. Med. Chem., 1998, 41, 3426-3434.
[21]
Olah, M.; Bologa, C.; Oprea, T.I. An automated PLS search for biologically relevant QSAR descriptors. J. Comput. Aided Mol. Des., 2004, 18(7-9), 437-449.
[22]
Ji, Y.; Shu, M.; Lin, Y.; Wang, Y.; Wang, R.; Hu, Y.; Lin, Z. Combined 3D-QSAR modeling and molecular docking study on azacycles CCR5 antagonists. J. Mol. Struct., 2013, 1045(5), 35-41.
[23]
Clark, M.; Iii, R.D.C.; Jones, D.M.; Patterson, D.E.; Simeroth, P.E. Comparative Molecular Field Analysis (CoMFA). 2. Toward its use with 3D-structural databases. Tetrahed. Comp. Methodol, 1990, 3(1), 47-59.
[24]
Chirico, N.; Gramatica, P. Real external predictivity of QSAR models. Part 2. New intercomparable thresholds for different validation criteria and the need for scatter plot inspection. J. Chem. Inf. Model., 2012, 52, 2044-2058.
[25]
Ludovici, D.W.; Kavash, R.W.; Kukla, M.J.; Ho, C.Y.; Ye, H.; De Corte, B.L.; Andries, K.; de Béthune, M.P.; Azijn, H.; Pauwels, R.; Moereels, H.E.; Heeres, J.; Koymans, L.M.; de Jonge, M.R.; Van Aken, K.J.; Daeyaert, F.F.; Lewi, P.J.; Das, K.; Arnold, E.; Janssen, P.A. Evolution of anti-HIV drug candidates. Part 2: Diaryltriazine (DATA) analogues. Bioorg. Med. Chem. Lett., 2001, 11(17), 2229.
[26]
Shen, M.; Zhou, S.; Li, Y.Y.; Li, P.X.; Pan, P.C.; Zhou, S.Y.; Zhang, L.L.; Li, S.; Hou, T.J. Discovery and optimization of triazine derivatives as ROCK1 inhibitors: Molecular docking, molecular dynamics simulations and free energy calculations. Mol. Biosyst., 2013, 9, 361-374.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 16
ISSUE: 2
Year: 2019
Page: [153 - 159]
Pages: 7
DOI: 10.2174/1570180815666180413152636
Price: $65

Article Metrics

PDF: 30
HTML: 2