Skip to main content

Advertisement

Springer Nature Link
Log in

Novel phosphatidylinositol 4-kinases III beta (PI4KIIIβ) inhibitors discovered by virtual screening using free energy models

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Abstract

Herein, the LASSBio Chemical Library is presented as a valuable source of compounds for screening to identify hits suitable for subsequent hit-to-lead optimization stages. A feature of the LASSBio Chemical Library worth highlighting is the fact that it is a smart library designed by medicinal chemists with pharmacological activity as the main priority. The great majority of the compounds part of this library have shown in vivo activity in animal models, which is an indication that they possess overall favorable bioavailability properties and, hence, adequate pharmacokinetic profiles. This, in turn, is supported by the fact that approximately 85% of the compounds are compliant with Lipinski’s rule of five and ca. 95% are compliant with Veber’s rules, two important guidelines for oral bioavailability. In this work it is presented a virtual screening methodology combining a pharmacophore-based model and an empirical Gibbs free energy-based model for the ligand–protein interaction to explore the LASSBio Chemical Library as a source of new hits for the inhibition of the phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ) enzyme, which is related to the development of viral infections (including enteroviruses, SARS coronavirus, and hepatitis C virus), cancers and neurological diseases. The approach resulted in the identification of two hits, LASSBio-1799 (7) and LASSBio-1814 (10), which inhibited the target enzyme with IC50 values of 3.66 μM and IC50 and 6.09 μM, respectively. This study also enabled the determination of the structural requirements for interactions with the active site of PI4KIIIβ, demonstrating the importance of both acceptor and donor hydrogen bonding groups for forming interactions with binding site residues Val598 and Lys549.

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
$34.99 /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 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
Fig. 4

Similar content being viewed by others

References

  1. Holenz J, Stoy P (2019) Advances in lead generation. Bioorg Med Chem Lett 29:517–524. https://doi.org/10.1016/j.bmcl.2018.12.001

    Article  CAS  PubMed  Google Scholar 

  2. Wermuth CG, Aladous D, Raboisson P, Rognan D (2015) The Practice of Medicinal Chemistry, 4th edn. London, Elsevier

    Google Scholar 

  3. Hersey A, Chambers J, Bellis L et al (2015) Chemical databases: curation or integration by user-defined equivalence? Drug Discov Today Technol 14:17–24. https://doi.org/10.1016/j.ddtec.2015.01.005

    Article  PubMed  PubMed Central  Google Scholar 

  4. Walters WP (2019) Virtual chemical libraries. J Med Chem 62:1116–1124. https://doi.org/10.1021/acs.jmedchem.8b01048

    Article  CAS  PubMed  Google Scholar 

  5. Follmann M, Briem H, Steinmeyer A et al (2019) An approach towards enhancement of a screening library: the Next Generation Library Initiative (NGLI) at Bayer: against all odds? Drug Discov Today 24:668–672. https://doi.org/10.1016/j.drudis.2018.12.003

    Article  CAS  PubMed  Google Scholar 

  6. Vieth M, Siegel MG, Higgs RE et al (2004) Characteristic physical properties and structural fragments of marketed oral drugs. J Med Chem 47:224–232. https://doi.org/10.1021/jm030267j

    Article  CAS  PubMed  Google Scholar 

  7. Ohno K, Nagahara Y, Tsunoyama K, Orita M (2010) Are there differences between launched drugs, clinical candidates, and commercially available compounds? J Chem Inf Model 50:815–821. https://doi.org/10.1021/ci100023s

    Article  CAS  PubMed  Google Scholar 

  8. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings 1PII of original article: S0169–409X(96), 00423–1. The article was originally published in Advanced Drug Delivery Reviews 23 (1997). Adv Drug Deliv Rev 23:3–26. https://doi.org/10.1016/S0169-409X(00)00129-0

    Article  CAS  Google Scholar 

  9. Veber DF, Johnson SR, Cheng H-Y et al (2002) Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 45:2615–2623. https://doi.org/10.1021/jm020017n

    Article  CAS  PubMed  Google Scholar 

  10. Wang Y, Xiao J, Suzek TO et al (2009) PubChem: a public information system for analyzing bioactivities of small molecules. Nucleic Acids Res 37:W623–W633. https://doi.org/10.1093/nar/gkp456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Irwin JJ, Shoichet BK (2005) ZINC: a free database of commercially available compounds for virtual screening. J Chem Inf Model 45:177–182. https://doi.org/10.1021/ci049714+

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Prestwick Chemical. https://www.prestwickchemical.com/libraries-screening-lib-pcl.html. Accessed 2 Jul 2019

  13. Wood A, Armour D (2005) The discovery of the CCR5 receptor antagonist, UK-427,857, a new agent for the treatment of HIV infection and AIDS. In: King FD (ed) Progress in medicinal chemistry. Elsevier, London, pp 239–271

    Google Scholar 

  14. LASSBio Chemical Library. https://www.lassbiochemicallibrary.com. Accessed 2 Jul 2019

  15. Richard AW, Frederick G (2011) Kinase drug discovery, 1st edn. Royal Society of Chemistry, Cambridge

    Google Scholar 

  16. Borawski J, Troke P, Puyang X et al (2009) Class III phosphatidylinositol 4-kinase alpha and beta are novel host factor regulators of hepatitis C virus replication. J Virol 83:10058–10074. https://doi.org/10.1128/JVI.02418-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Li J, Lu Y, Zhang J et al (2010) PI4KIIα is a novel regulator of tumor growth by its action on angiogenesis and HIF-1α regulation. Oncogene 29:2550–2559. https://doi.org/10.1038/onc.2010.14

    Article  CAS  PubMed  Google Scholar 

  18. Moorhead AM, Jung JY, Smirnov A et al (2010) Multiple host proteins that function in phosphatidylinositol-4-phosphate metabolism are recruited to the chlamydial inclusion. Infect Immun 78:1990–2007. https://doi.org/10.1128/IAI.01340-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Delang L, Paeshuyse J, Neyts J (2012) The role of phosphatidylinositol 4-kinases and phosphatidylinositol 4-phosphate during viral replication. Biochem Pharmacol 84:1400–1408. https://doi.org/10.1016/j.bcp.2012.07.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Clayton EL, Minogue S, Waugh MG (2013) Phosphatidylinositol 4-kinases and PI4P metabolism in the nervous system: roles in psychiatric and neurological diseases. Mol Neurobiol 47:361–372. https://doi.org/10.1007/s12035-012-8358-6

    Article  CAS  PubMed  Google Scholar 

  21. Waugh MG (2012) Phosphatidylinositol 4-kinases, phosphatidylinositol 4-phosphate and cancer. Cancer Lett 325:125–131. https://doi.org/10.1016/j.canlet.2012.06.009

    Article  CAS  PubMed  Google Scholar 

  22. Altan-Bonnet N, Balla T (2012) Phosphatidylinositol 4-kinases: hostages harnessed to build panviral replication platforms. Trends Biochem Sci 37:293–302. https://doi.org/10.1016/j.tibs.2012.03.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yang N, Ma P, Lang J et al (2012) Phosphatidylinositol 4-kinase IIIβ is required for severe acute respiratory syndrome coronavirus spike-mediated cell entry. J Biol Chem 287:8457–8467. https://doi.org/10.1074/jbc.M111.312561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Boura E, Nencka R (2015) Phosphatidylinositol 4-kinases: function, structure, and inhibition. Exp Cell Res 337:136–145. https://doi.org/10.1016/j.yexcr.2015.03.028

    Article  CAS  PubMed  Google Scholar 

  25. Fanfrlík J, Bronowska AK, Řezáč J et al (2010) A reliable docking/scoring scheme based on the semiempirical quantum mechanical PM6-DH2 method accurately covering dispersion and H-bonding: HIV-1 protease with 22 ligands. J Phys Chem B 114:12666–12678. https://doi.org/10.1021/jp1032965

    Article  CAS  PubMed  Google Scholar 

  26. Wang S, Milne GWA, Nicklaus MC et al (1994) Protein kinase C. Modeling of the binding site and prediction of binding constants. J Med Chem 37:1326–1338. https://doi.org/10.1021/jm00035a013

    Article  CAS  PubMed  Google Scholar 

  27. Murray CW, Verdonk ML (2002) The consequences of translational and rotational entropy lost by small molecules on binding to proteins. J Comput Aided Mol Des 16:741–753. https://doi.org/10.1023/a:1022446720849

    Article  CAS  PubMed  Google Scholar 

  28. Stewart JJP (1990) Reviews in computational chemistry. Wiley, Hoboken

    Google Scholar 

  29. SantAnna CMR (2009) Molecular modeling methods in the study and design of bioactive compounds: an introduction. Rev Virtual Química. https://doi.org/10.5935/1984-6835.20090007

    Article  Google Scholar 

  30. Menikarachchi L, Gascon J (2010) QM/MM approaches in medicinal chemistry research. Curr Top Med Chem 10:46–54. https://doi.org/10.2174/156802610790232297

    Article  CAS  PubMed  Google Scholar 

  31. Wollacott AM, Merz KM (2007) Assessment of semiempirical quantum mechanical methods for the evaluation of protein structures. J Chem Theory Comput 3:1609–1619. https://doi.org/10.1021/ct600325q

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. González R, Suárez CF, Bohórquez HJ et al (2017) Semi-empirical quantum evaluation of peptide: MHC class II binding. Chem Phys Lett 668:29–34. https://doi.org/10.1016/j.cplett.2016.12.015

    Article  CAS  Google Scholar 

  33. Cabeza de Vaca I, Qian Y, Vilseck JZ et al (2018) Enhanced Monte Carlo methods for modeling proteins including computation of absolute free energies of binding. J Chem Theory Comput 14:3279–3288. https://doi.org/10.1021/acs.jctc.8b00031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Oliveira FG, Sant’Anna CMR, Caffarena ER et al (2006) Molecular docking study and development of an empirical binding free energy model for phosphodiesterase 4 inhibitors. Bioorg Med Chem 14:6001–6011. https://doi.org/10.1016/j.bmc.2006.05.017

    Article  CAS  PubMed  Google Scholar 

  35. LaMarche MJ, Borawski J, Bose A et al (2012) Anti-hepatitis C virus activity and toxicity of type III phosphatidylinositol-4-kinase beta inhibitors. Antimicrob Agents Chemother 56:5149–5156. https://doi.org/10.1128/AAC.00946-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Waring MJ, Andrews DM, Faulder PF et al (2014) Potent, selective small molecule inhibitors of type III phosphatidylinositol-4-kinase α- but not β-inhibit the phosphatidylinositol signaling cascade and cancer cell proliferation. Chem Commun 50:5388–5390. https://doi.org/10.1039/C3CC48391F

    Article  CAS  Google Scholar 

  37. Mejdrová I, Chalupská D, Kögler M et al (2015) Highly selective phosphatidylinositol 4-kinase IIIβ inhibitors and structural insight into their mode of action. J Med Chem 58:3767–3793. https://doi.org/10.1021/acs.jmedchem.5b00499

    Article  CAS  PubMed  Google Scholar 

  38. Mejdrová I, Chalupská D, Plačková P et al (2017) Rational design of novel highly potent and selective phosphatidylinositol 4-kinase IIIβ (PI4KB) inhibitors as broad-spectrum antiviral agents and tools for chemical biology. J Med Chem 60:100–118. https://doi.org/10.1021/acs.jmedchem.6b01465

    Article  CAS  PubMed  Google Scholar 

  39. Rutaganira FU, Fowler ML, McPhail JA et al (2016) Design and structural characterization of potent and selective inhibitors of phosphatidylinositol 4 kinase IIIβ. J Med Chem 59:1830–1839. https://doi.org/10.1021/acs.jmedchem.5b01311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Šála M, Kögler M, Plačková P et al (2016) Purine analogs as phosphatidylinositol 4-kinase IIIβ inhibitors. Bioorg Med Chem Lett 26:2706–2712. https://doi.org/10.1016/j.bmcl.2016.04.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Halgren TA (1996) Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94. J Comput Chem 17:490–519

    Article  CAS  Google Scholar 

  42. Stewart JJP (2007) Optimization of parameters for semiempirical methods V: modification of NDDO approximations and application to 70 elements. J Mol Model 13:1173–1213. https://doi.org/10.1007/s00894-007-0233-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Berman HM (2000) The protein data bank. Nucleic Acids Res 28:235–242. https://doi.org/10.1093/nar/28.1.235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Burke JE, Inglis AJ, Perisic O et al (2014) Structures of PI4KIII complexes show simultaneous recruitment of Rab11 and its effectors. Science 344:1035–1038. https://doi.org/10.1126/science.1253397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Korb O, Stützle T, Exner TE (2009) Empirical scoring functions for advanced protein−ligand docking with PLANTS. J Chem Inf Model 49:84–96. https://doi.org/10.1021/ci800298z

    Article  CAS  PubMed  Google Scholar 

  46. Stewart JJP (2013) Optimization of parameters for semiempirical methods VI: more modifications to the NDDO approximations and re-optimization of parameters. J Mol Model 19:1–32. https://doi.org/10.1007/s00894-012-1667-x

    Article  CAS  PubMed  Google Scholar 

  47. Chambers CC, Hawkins GD, Cramer CJ, Truhlar DG (1996) Model for aqueous solvation based on class IV atomic charges and first solvation shell effects. J Phys Chem 100:16385–16398. https://doi.org/10.1021/jp9610776

    Article  CAS  Google Scholar 

  48. Cer RZ, Mudunuri U, Stephens R, Lebeda FJ (2009) IC50-to-Ki: a web-based tool for converting IC50 to Ki values for inhibitors of enzyme activity and ligand binding. Nucleic Acids Res 37:W441–W445. https://doi.org/10.1093/nar/gkp253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Nunes IKC (2013) Novos inibidores de fosfodiesterases 4 análogos de LASSBio-488 – desenho, síntese e análise comparativa de suas propriedades físico-químicas e cinéticas. PhD Thesis, Universidade Federal do Rio de Janeiro

  50. Lima L, Barreiro E (2005) Bioisosterism: a useful strategy for molecular modification and drug design. Curr Med Chem 12:23–49. https://doi.org/10.2174/0929867053363540

    Article  CAS  PubMed  Google Scholar 

  51. Lima LM, Barreiro EJ (2017) Beyond bioisosterism: new concepts in drug discovery. Comprehensive medicinal chemistry III. Elsevier, New York, pp 186–210

    Chapter  Google Scholar 

  52. Gilson MK, Zhou H-X (2007) Calculation of protein-ligand binding affinities. Annu Rev Biophys Biomol Struct 36:21–42. https://doi.org/10.1146/annurev.biophys.36.040306.132550

    Article  CAS  PubMed  Google Scholar 

  53. Kukic P, Farrell D, McIntosh LP et al (2013) Protein dielectric constants determined from NMR chemical shift perturbations. J Am Chem Soc 135:16968–16976. https://doi.org/10.1021/ja406995j

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Knight ZA, Feldman ME, Balla A et al (2007) A membrane capture assay for lipid kinase activity. Nat Protoc 2:2459–2466. https://doi.org/10.1038/nprot.2007.361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Keaney EP, Connolly M, Dobler M et al (2014) 2-Alkyloxazoles as potent and selective PI4KIIIβ inhibitors demonstrating inhibition of HCV replication. Bioorg Med Chem Lett 24:3714–3718. https://doi.org/10.1016/j.bmcl.2014.07.015

    Article  CAS  PubMed  Google Scholar 

  56. Lima LM, Frattani FS, dos Santos JL et al (2008) Synthesis and anti-platelet activity of novel arylsulfonate–acylhydrazone derivatives, designed as antithrombotic candidates. Eur J Med Chem 43:348–356. https://doi.org/10.1016/j.ejmech.2007.03.032

    Article  CAS  PubMed  Google Scholar 

  57. Silva TF (2012) Planejamento, síntese e avaliação farmacológica de uma nova série de derivados cicloalquil-N-Acilidrazonas análogos de LASSBio-294. MSc. Dissertation, Universidade Federal do Rio de Janeiro

  58. Barbosa MLDC, Lima LM, Tesch R et al (2014) Novel 2-chloro-4-anilino-quinazoline derivatives as EGFR and VEGFR-2 dual inhibitors. Eur J Med Chem 71:1–14. https://doi.org/10.1016/j.ejmech.2013.10.058

    Article  CAS  PubMed  Google Scholar 

  59. Thota S, Rodrigues DA, de Pinheiro P et al (2018) N-Acylhydrazones as drugs. Bioorg Med Chem Lett 28:2797–2806. https://doi.org/10.1016/j.bmcl.2018.07.015

    Article  CAS  PubMed  Google Scholar 

  60. Thorne N, Auld DS, Inglese J (2010) Apparent activity in high-throughput screening: origins of compound-dependent assay interference. Curr Opin Chem Biol 14:315–324. https://doi.org/10.1016/j.cbpa.2010.03.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the Brazilian funding agencies for the financial support involved in this work: Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq (INCT-INOFAR grant #465.249/2014-0; grant #309229/2018-9); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001; Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro—FAPERJ (Grant E-26/202.146/2015); Additionally, we would like to thank the Biomedical Sciences Institute of the Rio de Janeiro Federal University (ICB-UFRJ) for the infrastructure provided to develop this work.

Author information

Authors and Affiliations

  1. LASSBio – Laboratório de Avaliação e Síntese de Substâncias Bioativas, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, CCS, Cidade Universitária, Avenida Carlos Chagas Filho 373, Rio de Janeiro, RJ, ZIP 21941-910, Brazil

    Natalie M. Colodette, Lucas S. Franco, Rodolfo C. Maia, Harold H. Fokoue, Carlos Mauricio R. Sant’Anna & Eliezer J. Barreiro

  2. Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, CCS, Cidade Universitária, Rio de Janeiro, RJ, Brazil

    Natalie M. Colodette, Lucas S. Franco & Eliezer J. Barreiro

  3. Departamento de Química Fundamental, Instituto de Química, Universidade Federal Rural do Rio de Janeiro, Rodovia BR465, km 7, Seropédica, RJ, ZIP 23897-000, Brazil

    Carlos Mauricio R. Sant’Anna

  4. Programa de Pesquisas em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, CCS, Cidade Universitária, Rio de Janeiro, RJ, Brazil

    Eliezer J. Barreiro

Authors
  1. Natalie M. Colodette
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Lucas S. Franco
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Rodolfo C. Maia
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Harold H. Fokoue
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Carlos Mauricio R. Sant’Anna
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Eliezer J. Barreiro
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by NMC. The first draft of the manuscript was written by NMC and all authors revised and prepared following versions of the manuscript. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Eliezer J. Barreiro.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file 1 (DOCX 607 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Colodette, N.M., Franco, L.S., Maia, R.C. et al. Novel phosphatidylinositol 4-kinases III beta (PI4KIIIβ) inhibitors discovered by virtual screening using free energy models. J Comput Aided Mol Des 34, 1091–1103 (2020). https://doi.org/10.1007/s10822-020-00327-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-020-00327-9

Keywords