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Abstract

CoMFA, CoMSIA and molecular docking studies have been carried out for a set of 42 dihydroalkoxybenzyloxopyrimidine (DABO) derivatives for which anti-HIV activity values are available. In 3D-QSAR studies-comparative molecular field analysis (CoMFA) as well as comparative molecular similarity indices analysis (CoMSIA) have been performed. Both the QSAR model nicely explains the inhibitory activities of DABO derivatives as well as provides molecular level insights revealing which regions in 3D space around the molecules are more important for their anti HIV-activities. These models have a quite high square correlation coefficient (r2 = 0.817 for CoMFA and r2 = 0.943 for CoMSIA). A docking study of the highest active molecule into the binding site of the protein HIV-1 RT (PDB ID-1RT1) shows that hydrogen bonding between pyrimidine moiety of the ligand and the Lysine-101 moiety along with Valine-106 moiety of the HIV protein play most important role for stabilizing the ligand in the binding pocket of the protein.

Keywords

HIV Dihydroalkoxybenzyloxopyrimidine CoMFA CoMSIA Docking studies

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Kumar Sarkar, B., Sarkar, A., & Dipankar Jana, A. (2020). Non-Nucleoside HIV-1 Reverse Transcriptase Inhibition Activity of a Series of Dihydroalkoxybenzyloxopyrimidine (DABO) Derivatives: CoMFA, CoMSIA and Docking Studies. Asian Journal of Organic & Medicinal Chemistry, 5(3), 265–272. https://doi.org/10.14233/ajomc.2020.AJOMC-P289
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References

  1. E. De Clercq, New Approaches Toward Anti-HIV Chemotherapy, J. Med. Chem., 48, 1297 (2005); https://doi.org/10.1021/jm040158k
  2. H.C. Castro, N.I.V. Loureiro, M. Pujol-Luz, A.M.T. Souza, M.G. Albuquerque, D.O. Santos, L.M. Cabral, I.C. Frugulhetti and C.R. Rodrigues, HIV-1 Reverse Transcriptase: A Therapeutical Target in the Spotlight, Curr. Med. Chem., 13, 313 (2006); https://doi.org/10.2174/092986706775476089
  3. J. Balzarini, Current Status of the Non-nucleoside Reverse Transcriptase Inhibitors of Human Immunodeficiency Virus Type 1, Curr. Top. Med. Chem., 4, 921 (2004); https://doi.org/10.2174/1568026043388420
  4. E. De Clercq, HIV-Chemotherapy and -Prophylaxis: New Drugs, Leads and Approaches, Int. J. Biochem. Cell Biol., 36, 1800 (2004); https://doi.org/10.1016/j.biocel.2004.02.015
  5. E. De Clercq, Biochim. Biophys. Acta Mol. Basis Dis, 1587, 258 (2002); https://doi.org/10.1016/S0925-4439(02)00089-3
  6. C. Flexner, ed.: L.L. Brunton, Antiretroviral Agents and Treatment of HIV Infection in Goodman & Gilman: The Pharmacological Basis of Therapeutics, McGraw Hill: New York, NY, edn. 12; Section VIII, Chap. 9, pp 1273-1314 (2006).
  7. H.R. Xu, L. Fu, P. Zhan and X.Y. Liu, 3D-QSAR Analysis of a Series of S-DABO Derivatives as Anti-HIV Agents by CoMFA and CoMSIA, SAR QSAR Environ. Res., 27, 999 (2016); https://doi.org/10.1080/1062936X.2016.1233580
  8. H. Kubinyi, G. Folkers and Y.C. Martin, 3D QSAR in Drug Design, Kluwer: Dordrecht (1988).
  9. T. Puzyn, J. Leszczynski and M.T.D. Cronin, Recent Advances in QSAR Studies, Springer (2009).
  10. R.D. Cramer, D.E. Patterson and J.D. Bunce, Comparative Molecular Field Analysis (CoMFA). 1. Effect of Shape on Binding of Steroids to Carrier Proteins, J. Am. Chem. Soc., 110, 5959 (1988); https://doi.org/10.1021/ja00226a005
  11. I.A. Doytchinova and D.R. Flower, A Comparative Molecular Similarity Index Analysis (CoMSIA) Study Identifies an HLA-A2 Binding Supermotif, J. Comput. Aided Mol. Des., 16, 535 (2002); https://doi.org/10.1023/A:1021917203966
  12. G. Klebe, U. Abraham and T. Mietzner, Molecular Similarity Indices in a Comparative Analysis (CoMSIA) of Drug Molecules to Correlate and Predict Their Biological Activity, J. Med. Chem., 37, 4130 (1994); https://doi.org/10.1021/jm00050a010
  13. M. Batool, Protein Modelling & Molecular Docking, LAP Lambert Academic Publishing (2012).
  14. R. Bathini, S.K. Sivan, S. Fatima and V. Manga, Molecular Docking, MM/GBSA and 3D-QSAR Studies on EGFR Inhibitors, J. Chem. Sci., 128, 1163 (2016); https://doi.org/10.1007/s12039-016-1103-3
  15. A. Misra, S. Sharma, D. Sharma, S. Dubey, A. Mishra, D. Kishore and J. Dwivedi, Synthesis and Molecular Docking of Pyrimidine Incorpo-rated Novel Analogue of 1,5-Benzodiazepine as Antibacterial Agent, J. Chem. Sci., 130, 31 (2018); https://doi.org/10.1007/s12039-018-1430-7
  16. SYBYL-X 2.0, Tripos Inc, St. Louis.
  17. A. Mai, M. Artico, G. Sbardella, S. Massa, A.G. Loi, E. Tramontano, P. Scano and P. La Colla, Preparation and Anti-HIV-1 Activity of Thio Analogues of Dichydroalkoxybenzyloxopyrimidines, J. Med. Chem., 38, 3258 (1995); https://doi.org/10.1021/jm00017a010
  18. A. Mai, M. Artico, G. Sbardella, S. Quartarone, S. Massa, A.G. Loi, A. De Montis, F. Scintu, M. Putzolu and P. La Colla, Dihydro(alkylthio)-(naphthylmethyl)oxopyrimidines: Novel Non-Nucleoside Reverse Transcriptase Inhibitors of the S-DABO Series, J. Med. Chem., 40, 1447 (1997); https://doi.org/10.1021/jm960802y
  19. A. Mai, M. Artico, G. Sbardella, S. Massa, E. Novellino, G. Greco, A.G. Loi, E. Tramontano, M.E. Marongiu and P. La Colla, 5-Alkyl-2-(alkylthio)-6-(2,6-dihalophenylmethyl)-3,4-dihydropyrimidin-4(3H)-ones: Novel Potent and Selective Dihydro-alkoxy-benzyl-oxopyrimidine Derivatives, J. Med. Chem., 42, 619 (1999); https://doi.org/10.1021/jm980260f
  20. R. Ragno, A. Mai, G. Sbardella, M. Artico, S. Massa, C. Musiu, M. Mura, F. Marturana, A. Cadeddu and P. La Colla, Computer-Aided Design, Synthesis and Anti-HIV-1 Activity in vitro of 2-Alkylamino-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydro-5-alkylpyrimidin-4(3H)- ones as Novel Potent Non-Nucleoside Reverse Transcriptase Inhibitors, also Active against the Y181C Variant, J. Med. Chem., 47, 928 (2004); https://doi.org/10.1021/jm0309856
  21. M.D.M. Abdul-Hameed, A. Hamza, J. Liu and C.-G. Zhan, Combined 3D-QSAR Modeling and Molecular Docking Study on Indolinone Derivatives as Inhibitors of 3-Phosphoinositide-Dependent Protein Kinase-1, J. Chem. Inf. Model., 48, 1760 (2008); https://doi.org/10.1021/ci800147v
  22. D.M. Hawkins, S.C. Basak and D. Mills, Assessing Model Fit by Cross-Validation, J. Chem. Inf. Comput. Sci., 43, 579 (2003); https://doi.org/10.1021/ci025626i
  23. P.P. Roy and K. Roy, On Some Aspects of Variable Selection for Partial Least Squares Regression Models, QSAR Comb. Sci., 27, 302 (2008); https://doi.org/10.1002/qsar.200710043
  24. G.R. Desiraju, Supramolecular Synthons in Crystal Engineering-A New Organic Synthesis, Angew. Chem. Int. Ed. Engl., 34, 2311 (1995); https://doi.org/10.1002/anie.199523111