MUTANT P21 PEPTIDES COULD ACT AS AN IMPROVED CYCLIN A INHIBITORS FOR CANCER THERAPY: AN IN SILICO VALIDATION

  • Tarun Agarwal Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal 721302, India
  • Nithyanan Annamalai Advanced Medical and Dental Institute, Universiti Sains Malaysia, 13200, Bertam, Pulau Pinang, Malaysia
  • Hari Prasad Ronanki Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal 721302, India
  • Sandhya Butty Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal 721302, India
  • Tapas Kumar Maiti Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal 721302, India
  • Hasni Bin Arsad Advanced Medical and Dental Institute, Universiti Sains Malaysia, 13200, Bertam, Pulau Pinang, Malaysia

Abstract

Objective: The present study delineates the generation of mutant peptide library from a known anticancer peptide, p21 and in silico evaluation for their affinity towards cyclin. A substrate binding groove.


Methods: Mutant peptide library was created based on their AntiCP score and was docked with cyclin A using ClusPro2.0 web server. The docked structures were further simulated into an aqueous environment using Gromacs 4.5.6. Visualization was performed using PyMol software and interaction analysis was done using Discovery Studio Visualizer 4.1 Client and LigPlot plus tool.


Results: A total of 57 mutant peptides were generated; out of which only 3 namely, K3C (Lys3Cys), K3F (Lys3Phe), and K3W (Lys3Trp) had a greater affinity for cyclin A than WILD p21 peptide (HSKRRLIFS). Molecular dynamic simulation studies showed that the peptides remained docked into the substrate binding groove throughout the run. Among all the peptides, K3C showed a significantly higher negative binding energy with cyclin A as compared to WILD.


Conclusion: The overall results suggested that K3C mutant peptide had ~30 % higher affinity towards cyclin A and thus, could further be explored for its anticancer potential. The study also provides an insight into the crucial interactions governing the recognition of substrate binding groove of cyclin A for the development of novel peptide-based anticancer therapeutics.

Keywords: Target-based cancer therapy, Cyclin A, p21 mutant peptide library, Molecular docking, Molecular dynamic simulation

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References

1. Agarwal T, Annamalai N, Khursheed A, Maiti TK, Arsad HB, Siddiqui MH. Molecular docking and dynamic simulation evaluation of rohinitib-cantharidin based novel HSF1 inhibitors for cancer therapy. J Mol Graph Model 2015;61:141-9.
2. Chidambaram M, Manavalan R, Kathiresan K. Nanotherapeutics to overcome conventional cancer chemotherapy limitations. Int J Pharm Pharm Sci 2011;14:67-77.
3. Akhtar MJ, Ahamed M, Alhadlaq HA, Alrokayan SA, Kumar S. Targeted anticancer therapy: overexpressed receptors and nanotechnology. Clinica Chimica Acta 2014;436:78-92.
4. Lodish H, Berk A, Zipursky SL, Matsudaira P, Baltimore D, Darnell J. DNA damage and repair and their role in carcinogenesis; 2000.
5. Painter R. DNA damage and repair in eukaryotic cells. Genetics 1974;78:139-48.
6. Oren M. Regulation of the p53 tumor suppressor protein. J Biol Chem 1999;274:36031-4.
7. Goodsell DS. The molecular perspective: p53 tumor suppressor. Oncologist 1999;4:138-9.
8. Behera B, Mukherjee D, Agarwal T, Das J, Ghosh SK, Maiti TK. Cell penetrating peptides from agglutinin protein of Abrus precatorius facilitate the uptake of Imatinib mesylate. Colloids Surf B 2016;140:169-75.
9. Borghouts C, Kunz C, Groner B. Current strategies for the development of peptide?based anti?cancer therapeutics. J Pept Sci 2005;11:713-26.
10. Zheleva D, McInnes C, Gavine AL, Zhelev N, Fischer P, Lane D. Highly potent p21WAF1?derived peptide inhibitors of CDK?mediated pRb phosphorylation: delineation and structural insight into their interactions with cyclin a. ?J Pept Sci 2002;60:257-70.
11. R Pincus M, Fenelus M, Sarafraz Yazdi E, Adler V, Bowne W, Michl J. Anti-cancer peptides from ras-p21 and p53 proteins. Curr Pharm Des 2011;17:2677-98.
12. Fischer PM, Lane DP. Inhibitors of cyclin-dependent kinases as anti-cancer therapeutics. Curr Med Chem 2000;7:1213-45.
13. Russo AA, Jeffrey PD, Patten AK, Massague J, Pavletich NP. Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A–Cdk2 complex. Nature 1996;382:325-31.
14. Gulbis JM, Kelman Z, Hurwitz J, O'Donnell M, Kuriyan J. Structure of the C-terminal region of p21 WAF1/CIP1 complexed with human PCNA. Cell 1996;87:297-306.
15. Tyagi A, Kapoor P, Kumar R, Chaudhary K, Gautam A, Raghava G. In silico models for designing and discovering novel anticancer peptides. Sci Rep 2013;3:2984.
16. Kozakov D, Brenke R, Comeau SR, Vajda S. PIPER: an FFT?based protein docking program with pairwise potentials. Proteins: Struct Funct Bioinf 2006;65:392-406.
17. Comeau SR, Gatchell DW, Vajda S, Camacho CJ. ClusPro: an automated docking and discrimination method for the prediction of protein complexes. Bioinformatics 2004;20:45-50.
18. Anand Thiyagaraj JSS, Waheeta Sopper. Effect of toll-like receptor inhibitor imiquimod on IL1R1 interaction with IL1Ra and its SNP variant-an in silico approach. Int J Pharm Pharm Sci 2016;8:109-12.
19. Rakesh KR, Pandit DG, Tapan K Mukherjee. Identification of potential salmonella typhi beta-lactamase tem 1 inhibitors using peptidomimetics, virtual screening, and molecular dynamics simulations. Int J Pharm Pharm Sci 2018;10:91-6.
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How to Cite
Agarwal, T., N. Annamalai, H. P. Ronanki, S. Butty, T. K. Maiti, and H. B. Arsad. “MUTANT P21 PEPTIDES COULD ACT AS AN IMPROVED CYCLIN A INHIBITORS FOR CANCER THERAPY: AN IN SILICO VALIDATION”. International Journal of Pharmacy and Pharmaceutical Sciences, Vol. 11, no. 2, Dec. 2018, pp. 59-64, doi:10.22159/ijpps.2019v11i2.30577.
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