Skip to main content
SpringerLink
Log in

Computational design of novel AKT inhibitors

  • Original Article
  • Published:
Network Modeling Analysis in Health Informatics and Bioinformatics Aims and scope Submit manuscript

Abstract

The study entails the computational design of novel anticancer compounds which specifically targets the AKT signaling pathway by inhibit the AKT protein. The work was done by carrying out a molecular docking study on nine (9) identified approved FDA drugs collected from the bindingDB.org website. The results of the docking study revealed that A-674563 had the best-free energy of binding value of − 32.63 kcal/mol, while AT-7867 and AZD563 molecules were reported to have − 30.978 and − 27.668 kcal/mol binding energy value, respectively. Molecule A674563 was selected as lead compound further subjected to a structure-based drug design, where a fragment was incorporated or attached to the side chain of the lead and re-docked in the same binding pocket of the AKT receptor target. The results of our findings led to the identification of two novel compounds (molecules 5a and 7a), which were found to better inhibit AKT protein with a binding affinity values of − 36.015 kcal/mol and − 33.324 kcal/mol, respectively. Since their values were significantly better than that of the lead molecule especially when considering their stability in terms of the number of hydrogen bond they formed the amino acids in the AKT-binding pocket.

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
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Availability of data and material

All data and material are available upon request.

References

  • Bellacosa A, De Feo D, Godwin AK, Bell DW, Cheng JQ, Altomare DA, Masciullo V (1995) Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer 64(4):280–285

    Article  Google Scholar 

  • Brazil DP, Yang Z-Z, Hemmings BA (2004) Advances in protein kinase B signalling: AKTion on multiple fronts. Trends Biochem Sci 29(5):233–242

    Article  Google Scholar 

  • Chalhoub N, Baker SJ (2009) PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol 4:127–150

    Article  Google Scholar 

  • Cristiano BE, Chan JC, Hannan KM, Lundie NA, Marmy-Conus NJ, Campbell IG, Pearson RB (2006) A specific role for AKT3 in the genesis of ovarian cancer through modulation of G2-M phase transition. Can Res 66(24):11718–11725

    Article  Google Scholar 

  • Crouthamel M-C, Kahana JA, Korenchuk S, Zhang S-Y, Sundaresan G, Eberwein DJ, Kumar R (2009) Mechanism and management of AKT inhibitor-induced hyperglycemia. Clin Cancer Res 15(1):217–225

    Article  Google Scholar 

  • Davidson ER, Feller D (1986) Basis set selection for molecular calculations. Chem Rev 86(4):681–696

    Article  Google Scholar 

  • Dumble M, Crouthamel M-C, Zhang S-Y, Schaber M, Levy D, Robell K, Seefeld MA (2014) Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor. PLoS ONE 9(6):e100880

    Article  Google Scholar 

  • Feng Y, Rhodes PG, Bhatt AJ (2010) Hypoxic preconditioning provides neuroprotection and increases vascular endothelial growth factor A, preserves the phosphorylation of Akt-Ser-473 and diminishes the increase in caspase-3 activity in neonatal rat hypoxic–ischemic model. Brain Res 1325:1–9

    Article  Google Scholar 

  • Garcia-Echeverria C, Sellers W (2008) Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene 27(41):5511–5526

    Article  Google Scholar 

  • Hehre WJ, Huang WW (1995) Chemistry with computation: an introduction to SPARTAN. Wavefunction Inc., Irvine

    Google Scholar 

  • Jin J, Jin L, Lim SW, Yang CW (2016) Klotho deficiency aggravates tacrolimus-induced renal injury via the phosphatidylinositol 3-kinase-Akt-forkhead box protein O pathway. Am J Nephrol 43(5):357–365

    Article  Google Scholar 

  • Kallan NC, Spencer KL, Blake JF, Xu R, Heizer J, Bencsik JR, Risom T (2011) Discovery and SAR of spirochromane Akt inhibitors. Bioorg Med Chem Lett 21(8):2410–2414

    Article  Google Scholar 

  • Li Z, Wan H, Shi Y, Ouyang P (2004) Personal experience with four kinds of chemical structure drawing software: review on ChemDraw, ChemWindow, ISIS/Draw, and ChemSketch. J Chem Inf Comput Sci 44(5):1886–1890

    Article  Google Scholar 

  • Lipinski CA (2000) Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods 44(1):235–249

    Article  Google Scholar 

  • Luo J, Manning BD, Cantley LC (2003) Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 4(4):257–262

    Article  Google Scholar 

  • McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Franklin RA, Montalto G, Malaponte G (2012) Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascade inhibitors: how mutations can result in therapy resistance and how to overcome resistance. Oncotarget 3(10):1068

    Article  Google Scholar 

  • Neves MA, Totrov M, Abagyan R (2012) Docking and scoring with ICM: the benchmarking results and strategies for improvement. J Comput Aided Mol Des 26(6):675–686

    Article  Google Scholar 

  • Nitulescu GM, Van De Venter M, Nitulescu G, Ungurianu A, Juzenas P, Peng Q, Tsoukalas D (2018) The Akt pathway in oncology therapy and beyond. Int J Oncol 53(6):2319–2331

    Google Scholar 

  • OECD (2007) Guidance document on the validation of (quantitative) structure–activity relationships [(Q)SAR] models. Organisation for Economic Co-Operation and Development, Paris

    Google Scholar 

  • Rhodes N, Heerding DA, Duckett DR, Eberwein DJ, Knick VB, Lansing TJ, Robell K (2008) Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. Can Res 68(7):2366–2374

    Article  Google Scholar 

  • Rodgers SJ, Ferguson DT, Mitchell CA, Ooms LM (2017) Regulation of PI3K effector signalling in cancer by the phosphoinositide phosphatases. Biosci Rep 37(1):BSR20160432

    Article  Google Scholar 

  • Schäfer A, Horn H, Ahlrichs R (1992) Fully optimized contracted Gaussian basis sets for atoms Li to Kr. J Chem Phys 97(4):2571–2577

    Article  Google Scholar 

  • Song M, Bode AM, Dong Z, Lee M-H (2019) AKT as a therapeutic target for cancer. Can Res 79(6):1019–1031

    Article  Google Scholar 

  • Zhang X, Tang N, Hadden TJ, Rishi AK (2011) Akt, FoxO and regulation of apoptosis. Biochimica et Biophysica Acta (BBA) Mol Cell Res 1813(11):1978–1986

    Article  Google Scholar 

  • Zhao G-X, Pan H, Ouyang D-Y, He X-H (2015) The critical molecular interconnections in regulating apoptosis and autophagy. Ann Med 47(4):305–315

    Article  Google Scholar 

Download references

Acknowledgements

We would like to thank the management, BAZE University Abuja, Nigeria and specifically our Pro-Chancellor Baba Ahmed for all his support throughout the course of this research. We thank you and appreciate your efforts sir.

Funding

No funding was received.

Author information

Authors and Affiliations

  1. Department of Chemistry, Baze University, Abuja, Nigeria

    David Ebuka Arthur, Jibrin Noah Akoji, Riadh Sahnoun, Greatman C. Okafor, Karimatu Lami Abdullahi & Samira A. Abdullahi

  2. Department of Microbiology, Federal University of Technology, Minna, Nigeria

    Charles Mgbemena

Authors
  1. David Ebuka Arthur
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jibrin Noah Akoji
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Riadh Sahnoun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Greatman C. Okafor
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Karimatu Lami Abdullahi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Samira A. Abdullahi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Charles Mgbemena
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

DEA and RS designed the work, JNA and GCO collected the data, DEA and CM carried out the computational studies, RS and KLA analysed the result and finally DEA, SAA and CM wrote and edited the manuscript.

Corresponding author

Correspondence to David Ebuka Arthur.

Ethics declarations

Conflict of interests

No competing interests to declare.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Arthur, D.E., Akoji, J.N., Sahnoun, R. et al. Computational design of novel AKT inhibitors. Netw Model Anal Health Inform Bioinforma 10, 18 (2021). https://doi.org/10.1007/s13721-021-00296-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s13721-021-00296-5

Keywords

Search

Navigation