Citation: Jian-Bo TONG, Xing ZHANG, Shuai BIAN, Ding LUO. Drug Design, Molecular Docking, and ADMET Prediction of CCR5 Inhibitors Based on QSAR Study[J]. Chinese Journal of Structural Chemistry, ;2022, 41(2): 220200. doi: 10.14102/j.cnki.0254-5861.2011-3268 shu

Drug Design, Molecular Docking, and ADMET Prediction of CCR5 Inhibitors Based on QSAR Study

Jian-Bo TONG ^{a, b,,} ,
Xing ZHANG ^{a, b} ,
Shuai BIAN ^{a, b} ,
Ding LUO ^{a, b}

a.
College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi'an 710021, China
b.
Shaanxi Key Laboratory of Chemical Additives for Industry, Shaanxi University of Science and Technology, Xi'an 710021, China

Corresponding author: Jian-Bo TONG, jianbotong@aliyun.com
Received Date: 27 May 2021
Accepted Date: 5 July 2021

Fund Project: Innovation Supporting Plan of Shaanxi Province—Innovation Research Team 2018TD-015the Natural Science Foundation of Shaanxi Province 2019JM-237

Figures(11)

The chemokine receptor CCR5 is a main and necessary co-receptor for which HIV can recognize and enter the cells, and has been identified as a potential new target for the design of new anti-HIV therapeutic drugs. Highly active CCR5 inhibitors can prevent HIV-1 from entering target cells and block the process of infection. In this study, HQSAR and Topomer CoMFA methods were used to establish QSAR models for 75 1-(3, 3-diphenylpropyl)-piperidinyl and urea derivatives, and cross-validation and non-cross-validation were performed on the generated models. Two models with good statistical parameters and reliable prediction capabilities are obtained: (Topomer CoMFA: q² = 0.687, r² = 0.868, r_pred² = 0.623; HQSAR: q² = 0.781, r² = 0.921, r_pred² = 0.636). Contour maps and color code maps provide a lot of useful information for determining structural requirements that affect activity. Topomer search technology was used for virtual screening and molecular design. Surfex-dock method and ADMET technology were used to conduct molecular docking, oral bioavailability and toxicity prediction of the designed drug molecules. Results showed that A/ASN425, A/GLY198 and A/TRP427 may be the potential active residues of CCR5 inhibitors evaluated in this study, with 40 newly designed 1-(3, 3-diphenylpropyl)-piperidinyl and urea derivatives which have the main ADMET properties and can be used as a reliable anti-HIV inhibitor. These results provide a certain theoretical basis for the experimental verification of new compounds in the future.
- HIV,
- CCR5 inhibitors,
- Topomer CoMFA,
- HQSAR,
- ADMET
1. [1]
  Qian, Y. J.; Wu, Z. Y.; Chen, C.; Du, K. F.; Wei, W. B. Detection of HIV-1 viral load in tears of HIV/AIDS patients. Infection 2020, 48, 929–933. doi: 10.1007/s15010-020-01508-2
2. [2]
  Gao, R.; Fang, Q. J.; Zhang, X.; Xu, Q.; Ye, H. H.; Guo, W. Y.; He, J.; Chen, Y. H.; Wang, R. X.; Wu, Z. J; Yu, J. R5 HIV-1 gp120 activates p38 MAPK to induce rat cardiomyocyte injury by the CCR5 coreceptor. Pathobiology 2019, 86, 274–284. doi: 10.1159/000502238
3. [3]
  Hemkens, L. G.; Bucher, H. C. HIV infection and cardiovascular disease. Eur. Heart. J. 2014, 35, 1373–1381. doi: 10.1093/eurheartj/eht528
4. [4]
  Moore, J. P.; Stevenson, M. New targets for inhibitors of HIV-1 replication. Nat. Rev. Mol. Cell Bio. 2000, 1, 40–49. doi: 10.1038/35036060
5. [5]
  Wells, T. N. C.; Proudfoot, A. E.; Power, C. A. Chemokine receptors-the new frontier for AIDS research. Cell Chem. Biol. 1996, 3, 603−609.
6. [6]
  Palani, A.; Shapiro, S.; Clader, J. W. Biological evaluation and interconversion studies of rotamers of SCH 351125, an orally bioavailable CCR5 antagonist. Bioogr. Med. Chem. Lett. 2003, 13, 705–708. doi: 10.1016/S0960-894X(02)01062-4
7. [7]
  Shahlaei, M.; Fassihi, A. QSAR analysis of some 1-(3, 3-diphenylpropyl)-piperidinyl amides and ureas as CCR5 inhibitors using genetic algorithm-least square support vector machine. Med. Chem. Res. 2013, 22, 4384–4400. doi: 10.1007/s00044-012-0430-2
8. [8]
  Heravi, Y. E.; Sereshti, H.; Saboury, A. A. 3D QSAR studies, pharmacophore modeling, and virtual screening of diarylpyrazole-benzenesulfonamide derivatives as a template to obtain new inhibitors, using human carbonic anhydrase II as a model protein. J. Enzyme Inhib. Med. Chem. 2017, 32, 688−700. doi: 10.1080/14756366.2016.1241781
9. [9]
  Zheng, X.; He, M. X.; Tan, X.; Zheng, J.; Wang, F. Y.; Liu, S. 3D-quantitative structure-activity relationship and docking studies of coumarin derivatives as tissue kallikrein 7 inhibitors. J. Pharm. Pharmacol. 2017, 69, 1136−1144. doi: 10.1111/jphp.12751
10. [10]
  Li, S. L.; Bao, X. F.; Lu, C. H.; Ren, C. R.; Liu, G. C.; Du, H. G. Essential structural profile of novel adenosine derivatives as antiplatelet aggregation inhibitors based on 3D-QSAR analysis using CoMFA, CoMSIA, and SOMFA. Russ. J. Bioorg. Chem+. 2020, 46, 448−457. doi: 10.1134/S1068162020030103
11. [11]
  Fu, L.; Chen, Y.; Xu, C. M. 3D-QSAR, HQSAR, molecular docking, and new compound design study of 1, 3, 6-trisubstituted 1, 4-diazepan-7-ones as human KLK7 inhibitors. Med. Chem. Res. 2020, 29, 1012–1029. doi: 10.1007/s00044-020-02542-3
12. [12]
  Tong, J. B.; Shan, L.; Qin, S. S. QSAR studies of TIBO derivatives as HIV-1 reverse transcriptase inhibitors using HQSAR, CoMFA and CoMSIA. J. Mol. Struct. 2018, 1168, 56–64. doi: 10.1016/j.molstruc.2018.05.005
13. [13]
  Cheng, Y.; Mei, Z.; Tung, C. H. Studies on two types of PTP1β inhibitors for the treatment of type 2 diabetes: hologram QSAR for OBA and BBB analogues. Bioorg. Med. Chem. Lett. 2010, 20, 3329–3337. doi: 10.1016/j.bmcl.2010.04.033
14. [14]
  Castilho, M. S.; Postigo, M. P.; Montanari, C. A.; Oliva, G.; Andricopulo, A. D. Two- and three-dimensional quantitative structure-activity relationships for a series of purine nucleoside phosphorylase inhibitors. Bioorgan. Med. Chem. 2006, 14, 516−527. doi: 10.1016/j.bmc.2005.08.055
15. [15]
  Cumming, J. G.; Cooper, A. E.; Grime, K.; Logan, C. J.; McLaughlin, S.; Oldfield, J.; Shaw, J. S.; Tucker, H.; Winter, J.; Whittaker, D. Modulators of the human CCR5 receptor. Part 2: SAR of substituted 1-(3, 3-diphenylpropyl)-piperidinyl phenylacetamides. Bioorg. Med. Chem. Lett. 2005, 15, 5012–5015. doi: 10.1016/j.bmcl.2005.08.014
16. [16]
  Burrows, J. N.; Cumming, J. G.; Fillery, S. M.; Hamlin, G. A.; Hudson, J. A.; Jackson, R. J.; McLaughlin, S.; Shaw, J. S. Modulators of the human CCR5 receptor. Part 1: discovery and initial SAR of 1-(3, 3-diphenylpropyl)-piperidinyl amides and ureas. Bioorg. Med. Chem. Lett. 2005, 15, 25–28. doi: 10.1016/j.bmcl.2004.10.044
17. [17]
  Niu, B.; Lu, Y.; Wang, J. Y.; Hu, Y.; Chen, J. H.; Chen, Q.; He, G. W.; Zheng, L. F. 2D-SAR, Topomer CoMFA and molecular docking studies on avian influenza neuraminidase inhibitors. Comput. Struct. Biotec. 2019, 17, 39–48. doi: 10.1016/j.csbj.2018.11.007
18. [18]
  Zhu, W. L.; Chen, G.; Hu, L. H.; Luo, X. M.; Gui, C. S.; Luo, C.; Puah, C. M.; Chem, K. X.; Jiang, H. L. QSAR analyses on ginkgolides and their analogues using CoMFA, CoMSIA, and HQSAR. Bioorg. Med. Chem. 2005, 13, 313−322. doi: 10.1016/j.bmc.2004.10.027
19. [19]
  Huang, D. D.; Liu, Y. L.; Shi, B. Z.; Li, Y. T.; Wang, G. X.; Liang, G. Z. Comprehensive 3D-QSAR and binding mode of BACE-1 inhibitors using R-group search and molecular docking. J. Mol. Graph. Model. 2013, 45, 65−83. doi: 10.1016/j.jmgm.2013.08.003
20. [20]
  Shirmohammadi, M.; Mohammadinasab, E.; Bayat, Z. Prediction of lipophilicity of some quinolone derivatives by using quantitative structure-activity relationship. Curr. Drug. Discov. Technol. 2021, 18, 83–94. doi: 10.2174/1570163816666191108145026
21. [21]
  Xiang, Y. H.; Hou, Z. Y.; Zhang, Z. Y. Pharmacophore and QSAR studies to design novel histone deacetylase 2 inhibitors. Chem. Biol. Drug Des. 2012, 79, 760–770. doi: 10.1111/j.1747-0285.2012.01341.x
22. [22]
  Kiralj, R.; Ferreira, M. Basic validation procedures for regression models in QSAR and QSPR studies: theory and application. J. Brazil. Chem. Soc. 2009, 20, 770–787. doi: 10.1590/S0103-50532009000400021
23. [23]
  Aynur, O. A.; Nina, G. J.; Terry, W. S.; Mark, T. D. C. The better predictive model: high q² for the training set or low root mean square error of prediction for the test set? Mol. Inform. 2010, 24, 385–396.
24. [24]
  Golbraikh, A.; Tropsha, A. Beware of q²! J. Mol. Graph. Model. 2002, 20, 269–276. doi: 10.1016/S1093-3263(01)00123-1
25. [25]
  Sterling, T.; Irwin, J. J. ZINC 15-ligand discovery for everyone. J. Chem. Inf. Model. 2015, 55, 2324-2337. doi: 10.1021/acs.jcim.5b00559
26. [26]
  Tripathi, A.; Bankaitis, V. A. Molecular docking: from lock and key to combination lock. J. Mol. Med. Clin. App. 2017, 2, 1–9. doi: 10.1016/j.nhccr.2017.03.001
27. [27]
  Dudutiene, V.; Zubriene, A.; Kairys, V.; Smirnov, A.; Smirnoviene, J.; Leitans, J.; Kazaks, A.; Tars, K.; Manakova, L.; Grazulis, S.; Matulis, D. Isoform-selective enzyme inhibitors by exploring pocket size according to the lock-and-key Principle. Biophys. J. 2020, 119, 1513–1524. doi: 10.1016/j.bpj.2020.08.037
28. [28]
  Liu, J.; Li, Y.; Zhang, H. X.; Zhang, S. W.; Yang, L. Studies of H4R antagonists using 3D-QSAR, molecular docking and molecular dynamics. J. Mol. Model. 2012, 18, 991–1001. doi: 10.1007/s00894-011-1137-x
29. [29]
  Cleves, A. E.; Jain, A. N. Knowledge-guided docking: accurate prospective prediction of bound configurations of novel ligands using Surfex-Dock. J. Comput. Aided. Mol. Des. 2015, 29, 485–509. doi: 10.1007/s10822-015-9846-3
30. [30]
  Tong, J. B.; Luo, D.; Bian, S.; Zhang, X. Structural investigation of tetrahydropteridin analogues as selective PLK1 inhibitors for treating cancer through combined QSAR techniques, molecular docking, and molecular dynamics simulations. J. Mol. Liq. 2021, 335, 116235–17. doi: 10.1016/j.molliq.2021.116235
31. [31]
  Zhang, X. Z.; Xu, Y.; Jian, M. M.; Yang, K.; Ma, Z. Y. Synthesis, in vitro assays, molecular docking, theoretical ADMET prediction, and evaluation of 4-methoxy-phenylthiazole-2-amine derivatives as acetylcholinesterase inhibitors. Med. Chem. Res. 2019, 28, 1683–1693. doi: 10.1007/s00044-019-02405-6
32. [32]
  Jain, A. N. Surfex-Dock 2.1: robust performance from ligand energetic modeling, ring flexibility, and knowledge-based search. J. Comput. Aided. Mol. Des. 2007, 21, 281–306. doi: 10.1007/s10822-007-9114-2
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