[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Skip to main content

Advertisement

Springer Nature Link
Log in

4D-QSAR studies of coumarin derivatives as HIV-1 integrase 3′-processing inhibitors

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

In a pursuit of combating acquired immunodeficiency syndrome, the targets human immunodeficiency virus (HIV) protease, reverse transcriptase and HIV specific proteins were exhaustively explored. Resistance through mutations in these targets has impeded the further developments in HIV research. HIV-1 integrase (HIV-1 IN) has emerged as a newer target and 3′-processing, and strand transfer inhibition has proved potential intervention in HIV replication. In present study, in line with our interests in coumarin derivatives as potential bioactive molecules, 4D-quantitative structure–activity relationship (4D-QSAR) is proposed. Fifty-seven structurally diverse coumarin derivatives were subjected to 4D-QSAR studies. Quantum mechanics-based geometry optimization and molecular dynamics simulation were carried out on individual compound. The conformational ensemble generated for each compound was aligned with most active compound, and Coulombic and Lennard-Jones interaction energy descriptors were computed. After selecting the best variables in MATLAB, partial least square regression (PLS) analysis was carried out on 44 training set and 13 test set compounds. The model with ten latent variables was found best with R 2 calculated = 0.903015, R 2 cross-validated = 0.599553, R 2 predicted = 0.688525, root-mean-square error (RMSE) calculated = 0.21276, RMSE predicted = 0.371579 and prediction bias = −0.15362. Docking studies were carried out on AutoDock Vina, which were in good agreement with the PLS model, suggesting the importance of few descriptors of Coulombic interaction energy and VWD interactions with VAL79, VAL77, ARG199 and GLU157. These results may be useful in designing more potent HIV-1 IN inhibitors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
£29.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (United Kingdom)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  • Al-Mawsawi LQ, Fikkert V, Dayam R, Witvrouw M, Burke TR Jr, Borchers CH, Neamati N (2006) Discovery of a small-molecule HIV-1 integrase inhibitor-binding site. Proc Natl Acad Sci USA 103:10080–10085. doi:10.1073/pnas.0511254103

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bailly F, Queffelec C, Mbemba G, Mouscadet JF, Cotelle P (2005) Synthesis and HIV-1 integrase inhibitory activities of caffeic acid dimers derived from Salvia officinalis. Bioorg Med Chem Lett 15:5053–5056. doi:10.1016/j.bmcl.2005.07.091

    Article  CAS  PubMed  Google Scholar 

  • Ballabio D, Consonni V, Mauri A, Claeys-Bruno M, Sergent M, Todeschini R (2014) A novel variable reduction method adapted from space-filling designs. Chemom Intell Lab Syst 136:147–154

    Article  CAS  Google Scholar 

  • Berendsen HJC, van der Spoel D, van Drunen R (1995) GROMACS: a message-passing parallel molecular dynamics implementation. Comput Phys Commun 91:43–56

    Article  CAS  Google Scholar 

  • Chiang CC, Mouscadet JF, Tsai HJ, Liu CT, Hsu LY (2007) Synthesis and HIV-1 integrase inhibition of novel bis- or tetra-coumarin analogues. Chem Pharm Bull 55:1740–1743

    Article  CAS  PubMed  Google Scholar 

  • Cramer RD III, Patterson DE, Bunce JD (1988) Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J Am Chem Soc 110:5959–5967

    Article  CAS  PubMed  Google Scholar 

  • Curran JW (1983) AIDS—two years later. N Engl J Med 309:609–611

    Article  CAS  PubMed  Google Scholar 

  • Dijkstra TK (2010) Latent variables and indices: herman wold’s basic design and partial least squares. In: Vinzi VE, Chin WW, Henseler J, Wang H (eds) Handbook of partial least squares, 1st edn. Springer, NewYork, pp 23–46

    Chapter  Google Scholar 

  • Free SM, Wilson JWA (1964) Mathematical contribution to structure-activity studies. J Med Chem 7:395–399

    Article  CAS  PubMed  Google Scholar 

  • Granovsky AA, Firefly version 8.0, www http://classic.chem.msu.su/gran/firefly/index.html

  • Hansch C, Fujita TA (1964) Method for the correlation of biological activity and chemical structure. J Am Chem Soc 86:1616

    Article  CAS  Google Scholar 

  • Hess B, Kutzner C, van der Spoel D, Lindahl E (2008) GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput 4:435–447

    Article  CAS  Google Scholar 

  • Hopfinger A, Wang S, Tokarski J, Jin B, Albuquerque M, Madhav P, Duraiswami C (1997) Construction of 3D-QSAR models using the 4D-QSAR analysis formalism. J Am Chem Soc 119:10509–10524

    Article  CAS  Google Scholar 

  • Jaskolski M, Alexandratos JN, Bujacz G, Wlodawer A (2011) Structural studies of retroviral integrase. In: Neamati N (ed) HIV-1 integrase: mechanism and inhibitor design, 1st edn. Wiley, New York, pp 35–49

    Chapter  Google Scholar 

  • Johnson VA, Brun-Vezinet F, Clotet B, Gunthard HF, Kuritzkes DR, Pillay D, Schapiro JM, Richman DD (2010) Update of the drug resistance mutations in HIV-1. Top HIV Med 18:156–163

    PubMed  Google Scholar 

  • Klebe G, Abraham U, Mietzner T (1994) Molecular similarity indices in a comparative analysis (CoMSIA) of drug molecules to correlate and predict their biological activity. J Med Chem 37:4130–4146

    Article  CAS  PubMed  Google Scholar 

  • Korolev SP, Agapkina YY, Gottikh MB (2011) Clinical use of inhibitors of HIV-1 integration: problems and prospects. Acta Naturae 3:12–28

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kostova I, Raleva S, Genova P, Argirova R (2006) Structure-activity relationships of synthetic coumarins as HIV-1 inhibitors. Bioinorg Chem Appl 2006:68274. doi:10.1155/BCA/2006/68274

    PubMed Central  Google Scholar 

  • Liu M, Cong XJ, Li P, Tan JJ, Chen WZ, Wang CX (2009) Study on the inhibitory mechanism and binding mode of the hydroxycoumarin compound NSC158393 to HIV-1 integrase by molecular modeling. Biopolymers 91:700–709. doi:10.1002/bip.21211

    Article  CAS  PubMed  Google Scholar 

  • Mahajan DH, Pannecouque C, De Clercq E, Chikhalia KH (2009) Synthesis and studies of new 2-(coumarin-4-yloxy)-4,6-(substituted)-S-triazine derivatives as potential anti-HIV agents. Arch Pharm 342:281–290. doi:10.1002/ardp.200800149

    Article  CAS  Google Scholar 

  • Mao PCM, Mouscadet JF, Leh H, Auclair C, Hsu LY (2002) Chemical modification of coumarin dimer and HIV-1 integrase inhibitory activity. Chem Pharm Bull 50:1634–1637. doi:10.1248/cpb.50.1634

    Article  CAS  PubMed  Google Scholar 

  • Martins JPA, Barbosa EG, Pasqualoto KFM, Ferreira MMC (2009) LQTA-QSAR: a new 4D-QSAR methodology. J Chem Inf Model 49:1428–1436

    Article  CAS  PubMed  Google Scholar 

  • Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) Autodock4 and AutoDockTools4: automated docking with selective receptor flexiblity. J Comput Chem 16:2785–2791

    Article  Google Scholar 

  • Nunthaboot N, Tonmunphean S, Parasuk V, Wolschann P, Kokpol S (2006) Three-dimensional quantitative structureeactivity relationship studies on diverse structural classes of HIV-1 integrase inhibitors using CoMFA and CoMSIA. Eur J Med Chem 41:1359–1372

    Article  CAS  PubMed  Google Scholar 

  • Olmedo D, Sancho R, Bedoya LM, Lopez-Perez JL, Del Olmo E, Munoz E, Alcami J, Gupta MP, San Feliciano A (2012) Molecules 17:9245–9257. doi:10.3390/molecules17089245

    Article  CAS  PubMed  Google Scholar 

  • Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612

    Article  CAS  PubMed  Google Scholar 

  • Pronk S, Paill S, Schulz R, Larsson P, Bjelkmar P, Apostolov R, Shirts MR, Smith JC, Kasson PM, van der Spoel D, Hess B, Lindahl E (2013) GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics 29:845–854

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Schmidt MW, Baldridge KK, Boatz JA, Elbert ST, Gordon MS, Jensen JH, Koseki S, Matsunaga N, Nguyen KA, Su S, Windus TL, Dupuis M, Montgomery JA (1993) General atomic and molecular electronic structure system. J Comput Chem 14:1347–1363

    Article  CAS  Google Scholar 

  • Schroder AR, Shinn P, Chen H, Berry C, Ecker JR, Bushman F (2002) HIV-1 integration in the human genome favors active genes and local hotspots. Cell 10:521–529

    Article  Google Scholar 

  • Schuttelkopf AW, van Aalten DMF (2004) PRODRG: a tool for high-throughput crystallography of protein–ligand complexes. Acta Crystallogr D 60:1355–1363

    Article  PubMed  Google Scholar 

  • Spino C, Dodier M, Sotheeswaran S (1998) Anti-HIV coumarins from Calophyllum seed oil. Bioorg Med Chem Lett 8:3475–3478

    Article  CAS  PubMed  Google Scholar 

  • Su C, Mouscadet J, Chiang C, Tsai H, Hsu L (2006) HIV-1 integrase inhibition of biscoumarin analogues. Chem Pharm Bull 54:682–686

    Article  CAS  PubMed  Google Scholar 

  • Tewtrakul S, Subhadhirasakul S, Cheenpracha S, Karalai C (2007) HIV-1 protease and HIV-1 integrase inhibitory substances from Eclipta prostrata. Phytother Res 21:1092–1095

    Article  CAS  PubMed  Google Scholar 

  • Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J Comput Chem 31:455–461. doi:10.1002/jcc.21334

    CAS  PubMed Central  PubMed  Google Scholar 

  • U.S. Food and Drug Administration. http://www.fda.gov/downloads/drugs/developmentapprovalprocess/developmentresources/ucm385696.pdf Accessed 15 July 2014

  • Zhao H, Neamati N, Hong H, Mazumder A, Wang S, Sunder S, Milne GWA, Pommier Y, Burke TR Jr (1997) Coumarin-based inhibitors of HIV integrase-1. J Med Chem 40:242–249

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We acknowledge constant encouragement of Prof. M. N. Navale, President, Sinhgad Technical Education Society and Matteo Cassotti, Milano Chemometrics and QSAR Research Group, Department of Earth and Environmental Sciences, University of Milano-Bicocca for helpful suggestions in MATLAB usage.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, Sinhgad Technical Education Society’s Smt. Kashibai Navale College of Pharmacy, Pune-Saswad Road, Kondhwa (Bk), Pune, 411048, Maharashtra, India

    Rajesh B. Patil & Sanjay D. Sawant

Authors
  1. Rajesh B. Patil
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sanjay D. Sawant
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rajesh B. Patil.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Patil, R.B., Sawant, S.D. 4D-QSAR studies of coumarin derivatives as HIV-1 integrase 3′-processing inhibitors. Med Chem Res 24, 3062–3076 (2015). https://doi.org/10.1007/s00044-015-1359-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-015-1359-z

Keywords

Search

Navigation