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.
Highlights
In the past few decades, cancer has emerged as a leading cause of death worldwide
Zheleva et al have already demonstrated that the peptides derived from the C-terminus of p21 could effectively interact with cyclin A through its cyclin groove recognition sequence “SKRRLIF” [10]
The results demonstrated that the substrate binding groove was formed by α1, α3 and α4 helixes in the N-terminal domain of cyclin A
Summary
In the past few decades, cancer has emerged as a leading cause of death worldwide. Annually, cancer causes an estimated death of 5.5 lakh people and ~8 lakh new cases are at its risk [1, 2]. In addition to cancer cells, these therapies are detrimental to the healthy cells and further result in many other systemic side-effects. DNA damage activates tumor suppressor cascade resulting in either repair or growth arrest or apoptosis of the damaged cell [4, 5]. DNA damage is generally associated with the activation of p53 which in-turn activates a series of other proteins including DNA repair proteins, cell proliferation blockers and apoptosis-inducing proteins [6, 7]. Cancerous conditions are associated with the aberrant version of either of these transcription factors; making the cell incapable to sense DNA damage and/or any deleterious mutation, leading to an uncontrolled growth and transformation of the damaged cells
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