Skip to main content

Advertisement

SpringerLink
Log in

Dual acting HIV inhibitors: integrated rational in silico design strategy

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

Abstract

In silico pharmacophore and structure-based drug design guided by binding mode analysis and molecular dynamics simulations is an effective approach for identifying novel potent and selective inhibitors. Herein, we demonstrated a unique strategy for developing dual acting inhibitors against HIV-1 protease and reverse transcriptase via an integrated computational protocol that relies on “loop docking” and molecular dynamics simulations, the designed targets exhibited binding affinities comparable to, and in some cases better than, known active reference drugs.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Ahmed SM, Kruger HG, Govender T, Maguire GE, Sayed Y, Ibrahim MA, Naicker P, Soliman ME (2013) Comparison of the molecular dynamics and calculated binding free energies for nine FDA-approved HIV-1 PR drugs against subtype B and C-SA HIV PR. Chem Biol Drug Des 81:208–218

    Article  CAS  PubMed  Google Scholar 

  • Appelt K (1993) Crystal structures of HIV-1 protease-inhibitor complexes. Perspect Drug Discov Des 1(1):23–48. doi:10.1007/bf02171654

    Article  CAS  Google Scholar 

  • Bacheler LT (1999) Resistance to non-nucleoside inhibitors of HIV-I reverse transcriptase. Drug Resist Update 2(1):56–67

    Article  CAS  Google Scholar 

  • Brik A, Wong C (2003) HIV-1 protease: mechanism and drug discovery. Org Biomol Chem 1:5–14

    Article  CAS  PubMed  Google Scholar 

  • Case DA, Cheatham TE, Darden T, Gohlke H, Luo R, Merz KM, Onufriev A, Simmerling C, Wang B, Woods RJ (2005) The Amber biomolecular simulation programs. J Comput Chem 26(16):1668–1688. doi:10.1002/jcc.20290

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Damm KL, Ung PM, Quintero JJ, Gestwicki JE, Carlson HA (2008) A poke in the eye: inhibiting HIV-1 protease through its flap-recognition pocket. Biopolymers 89:643–652

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gemma S, Gabellieri E, Huleatt P, Fattorusso C, Borriello M, Catalanotti B, Butini S, De Angelis M, Novellino E, Nacci V, Belinskaya T, Saxena A, Campiani G (2006) Discovery of huperzine A-tacrine hybrids as potent inhibitors of human cholinesterases targeting their midgorge recognition sites. J Med Chem 49(11):3421–3425

    Article  CAS  PubMed  Google Scholar 

  • Groneberg RD, Burns CJ, Morrissette MM, Ullrich JW, Morris RL, Darnbrough S, Djuric SW, Condon SM, McGeehan GM, Labaudiniere R, Neuenschwander K, Scotese AC, Kline JA (1999) Dual inhibition of phosphodiesterase 4 and matrix metalloproteinases by an (arylsulfonyl)hydroxamic acid template. J Med Chem 42(4):541–544

    Article  CAS  PubMed  Google Scholar 

  • Hanwell MD, Curtis DE, Lonie DC, Vandermeersch T, Zurek E, Hutchison GR (2012) Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. J Cheminform 4:1–17

    Article  Google Scholar 

  • Hawkins PCD, Skillman AG, Warren GL, Ellingson BA, Stahl MT (2010) Conformer generation with OMEGA: algorithm and validation using high quality structures from the protein databank and Cambridge structural database. J Chem Inf Model 50:572–584

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Honarparvar B, Makatini MM, Pawar SA, Petzold K, Soliman ME, Arvidsson PI, Sayed Y, Govender T, Maguire GE, Kruger HG (2012) Pentacycloundecane-diol-based HIV-1 protease inhibitors: biological screening, 2D NMR, and molecular simulation studies. ChemMedChem 7(6):1009–1019

    Article  CAS  PubMed  Google Scholar 

  • Karpoormath R, Sayed Y, Govender P, Govender T, Kruger HG, Soliman ME, Maguire GE (2012) Pentacycloundecane derived hydroxy acid peptides: a new class of irreversible non-scissile ether bridged type isoster as potential HIV-1 wild type C-SA protease inhibitors. Bioorg Chem 40(1):19–29. doi:10.1016/j.bioorg.2011.08.002

    Article  CAS  PubMed  Google Scholar 

  • Kawanishi Y, Ishihara S, Tsushima T, Seno K, Miyagoshi M, Hagishita S, Ishikawa M, Shima N, Shimamura M, Ishihara Y (1996) Synthesis and pharmacological evaluation of highly potent dual histamine H-2 and gastrin receptor antagonists. Bioorg Med Chem Lett 6(13):1427–1430

    Article  CAS  Google Scholar 

  • Lewis WG, Green LG, Grynszpan F, Radic Z, Carlier PR, Taylor P, Finn MG, Sharpless KB (2002) Click chemistry in situ: acetylcholinesterase as a reaction vessel for the selective assembly of a femtomolar inhibitor from an array of building blocks. Angew Chem Int Ed Engl 41(6):1053–1057

    Article  CAS  PubMed  Google Scholar 

  • Makatini M, Petzold K, Sriharsha NS, Ndlovu N, Soliman MES, Honarparvar B, Parboosing R, Naidoo A, Arvidsson PI, Sayed Y, Govender P, Maguire GEM, Kruger HG, Govender T (2011a) Synthesis and structural studies of pentacycloundecane-based HIV-1 PR inhibitors: a hybrid 2D-NMR and docking/QM/MM/MD approach. Eur J Med Chem 46(9):3976–3985

    Article  CAS  PubMed  Google Scholar 

  • Makatini M, Petzold K, Sriharsha S, Soliman MES, Honarparvar B, Arvidson PI, Sayed Y, Govender P, Maguire GEM, Kruger H, Govender T (2011b) Pentacycloundecane-based Inhibitors of wild-type C-South African HIV protease. Bioorg Med Chem Lett 15(21):2274–2277. doi:10.1016/j.bmcl.2011.02.105

    Article  Google Scholar 

  • Makatini MM, Petzold K, Alves CN, Arvidsson PI, Honarparvar B, Govender P, Govender T, Kruger HG, Sayed Y, Jeronimolameira, Maguire GE, Soliman MES (2013) Synthesis, 2D-NMR and molecular modelling studies of pentacycloundecane lactam-peptides and peptoids as potential HIV-1 wild type C-SA protease inhibitors. J Enzym Inhib Med Chem 28(1):78–88. doi:10.3109/14756366.2011.633907

    Article  CAS  Google Scholar 

  • Mbisa JL, Martin SA, Cane PA (2011) Patterns of resistance development with integrase inhibitors in HIV. Infect drug resist 4:65–76

    PubMed Central  CAS  PubMed  Google Scholar 

  • Morphy R, Rankovic Z (2009) Designing multiple ligands—medicinal chemistry strategies and challenges. Curr Pharm Des 15(6):587–600

    Article  CAS  PubMed  Google Scholar 

  • Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19:1639–1662

    Article  CAS  Google Scholar 

  • Munoz-Torrero D, Camps P (2006) Dimeric and hybrid anti-Alzheimer drug candidates. Curr Med Chem 13(4):399–422

    Article  CAS  PubMed  Google Scholar 

  • Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD (1998) Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 338(13):853–860

    Article  PubMed  Google Scholar 

  • Pani A, Loi AG, Mura M, Marceddu T, La Colla P, Marongiu ME (2002) Targeting HIV: old and new players. Curr Drug Targets Infect Disord 2(1):17–32

    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 

  • Ryckmans T, Balancon L, Berton O, Genicot C, Lamberty Y, Lallemand B, Pasau P, Pirlot N, Quere L, Talaga P (2002) First dual NK1 antagonists-serotonin reuptake inhibitors: synthesis and SAR of a new class of potential antidepressants. Bioorg Med Chem Lett 12(2):261–264

    Article  CAS  PubMed  Google Scholar 

  • Schinazi RF, Hernandez-Santiago BI, Hurwitz SJ (2006) Pharmacology of current and promising nucleosides for the treatment of human immunodeficiency viruses. 71:322–334. Erratum in Antiviral Res 72 (3):256–256

    Google Scholar 

  • Thomsen R, Christensen M (2006) MolDock: a new technique for high-accuracy molecular docking. J Med Chem 1:3315–3321

    Article  Google Scholar 

  • Wallace AC, Laskowski RA, Thornton JM (1995) Ligplot—a program to generate schematic diagrams of protein ligand interactions. Protein Eng 8(2):127–134

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto M, Ikeda S, Kondo H, Inoue S (2002) Design and synthesis of dual inhibitors for matrix metalloproteinase and cathepsin. Bioorg Med Chem Lett 12(3):375–378

    Article  CAS  PubMed  Google Scholar 

  • Yeni P (2006) Update on HAART in HIV. J Hepatol 44:S100–S103

    Article  CAS  PubMed  Google Scholar 

  • Young B, Kuritzkes DR (2002) Resistance to HIV-1 protease inhibitors. Infect Dis Ther 25:257–282

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa

    Suri Moonsamy & Mahmoud E. S. Soliman

Authors
  1. Suri Moonsamy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mahmoud E. S. Soliman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mahmoud E. S. Soliman.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Moonsamy, S., Soliman, M.E.S. Dual acting HIV inhibitors: integrated rational in silico design strategy. Med Chem Res 23, 682–689 (2014). https://doi.org/10.1007/s00044-013-0670-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-013-0670-9

Keywords

Search

Navigation