Advertisement

Medicinal Chemistry Research

, Volume 22, Issue 6, pp 2795–2801 | Cite as

Predictive QSAR modeling on tetrahydropyrimidine-2-one derivatives as HIV-1 protease enzyme inhibitors

  • Jimish R. PatelEmail author
  • Laxman M. Prajapati
Original Research

Abstract

QSAR model development of 51 tetrahydropyrimidine-2-one was carried out to predict HIV-1 protease receptors inhibitors activity. Physicochemical parameters were calculated using DRAGON descriptor software, version 5.5. Stepwise multiple linear regression analysis was applied to derive QSAR models, which were further evaluated for statistical significance and predictive power by internal and external validation. The best quantitative structure activity relationship model having a correlation coefficient (R 2) of 0.824, cross-validated correlation coefficient (Q 2) of 0.773, and \( R_{pred}^{2} \) of 0.910 was selected. The predictive ability of the selected model was also confirmed by leave-one-out cross-validation. The QSAR model indicates that the descriptors (RDF010u, RDF010m, TPSA (NO), F04[C–N]) play an important role in enzyme binding. The information derived from the present study may be useful in the design of more potent substituted tetrahydropyrimidine-2-one.

Keywords

QSAR Tetrahydropyrimidine-2-one HIV-1 protease inhibitors Multiple linear regressions HIV 

References

  1. Adachi M (2009) Structure of HIV-1 protease in complex with potent inhibitor KNI-272 determined by high-resolution X-ray and neutron crystallography. Proc Natl Acad Sci USA 12:4641–4646CrossRefGoogle Scholar
  2. Ala PJ, Huston E, Klabe M, McCabe DD, Duke JL, Rizzo CJ, Korant BD, Delos Key RJ, Lam PYS, Hodge NC, Change CH (1997) Molecular basis of HIV-1 protease drug resistance: structural analysis of mutant protease complexed with cyclic urea inhibitors. Biochemistry 36:1573–1580PubMedCrossRefGoogle Scholar
  3. Boden D, Markowitz M (1998) Resistance to human immunodeficiency virus type 1 protease inhibitors. Antimicrob Agents Chemother 42:2775–2783PubMedGoogle Scholar
  4. Chen X (2003) Synthesis and SAR studies of potent HIV protease inhibitors containing novel dimethylphenoxyl acetates as P2 ligands. Bioorg Med Chem Lett 13:3657–3660PubMedCrossRefGoogle Scholar
  5. Condra JH, Schleif WA, Blahy OM, Gadryelski LJ, Graham DJ, Quintero JC, Rhodes HL, Roth E, Shivaprahash M, Titus D, Yang T, Teppler H, Squires KE, Deutsch PJ, Emini EA (1995) In vivo emergence of HIV-1 variants resistant multiple protease inhibitors. Nature 374:569–571PubMedCrossRefGoogle Scholar
  6. CS Chem Office (2004) Version 8.0, Cambridge Soft Corporation, Software Publishers Association, Washington, DCGoogle Scholar
  7. DRAGON for Windows (2007) ver. 5.5, Talete srl, MilanoGoogle Scholar
  8. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (2011). http://aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=7&ClassID=1. Accessed 17 Oct 2011
  9. Gupta AK, Arockia BM, Kaskhedikar SG (2004) VALSTAT: validation program for quantitative structure activity relationship studies. Indian J Pharm Sci 66:396–402Google Scholar
  10. Hemmer MC, Steinhauer V, Gasteiger J (1999) Deriving the 3D structure of organic molecules from their infrared spectra. Vib Spectrosc 19:151–164CrossRefGoogle Scholar
  11. Nair AC, Philippa J, Wang X, Miertus S, William J (2002) Welsh computational studies on tetrahydropyrimidine-2-one HIV-1 protease inhibitors: improving three-dimensional quantitative structure–activity relationship comparative molecular field analysis models by inclusion of calculated inhibitor- and receptor-based properties. J Med Chem 45:973–983PubMedCrossRefGoogle Scholar
  12. Rang HP, Dale MM, Ritter JM, Flower RJ (2007) Rang and Dale’s pharmacology. Churchill Livingstone/Elsevier, PhiladelphiaGoogle Scholar
  13. Stephen C, Peterangel O, Paul G, Seybol D (2004) Synergistic interactions among QSAR descriptors. Int J Quantum Chem 96:1–9CrossRefGoogle Scholar
  14. Thompson MA, Aberg JA, Cahn P et al (2010) Antiretroviral treatment of adult HIV infection: recommendations of the International AIDS Society—USA panel. JAMA 304(3):304–321CrossRefGoogle Scholar
  15. WHO/UNAIDS (2003) AIDS epidemic update. WHO/UNAIDS, GenevaGoogle Scholar
  16. Williams IG (2003) Int J Clin Pract 57:890–897PubMedGoogle Scholar
  17. Yanchunas J (2005) Molecular basis for increased susceptibility of isolates with atazanavir resistance conferring substitution I50L to other protease inhibitors. Antimicrob Agent Chemother 40:3825–3832CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Department of Pharmaceutical ChemistryShri B M Shah College of Pharmaceutical Education and ResearchModasaIndia

Personalised recommendations