Design of Novel Imidazopyrazine Derivative against Breast Cancer <i>via</i> Targeted NPY1R Antagonist

Author(s):

Vidya Niranjan*, Vibha R, Sarah Philip, Akshay Uttarkar, Raviraj Kusanur and Jitendra Kumar*   Pages 1783 - 1793 ( 11 )

Abstract:

<p>Introduction: Breast cancer is the most frequent malignancy in women with more than one in ten new cancer diagnoses each year. Synthetic products are a key source for the identification of new anticancer medicines and drug leads. </p><p> Objectives: Imidazopyrazine is a highly favored skeleton for the design of new anticancer drugs. <i>In silico</i> designed derivatives were screened using computer aided drug design techniques and validated using MTT assay. </p><p> Methods: A template-based methodology was used in the current work to create novel Imidazopyrazine derivatives, targeting the NPY1R protein. Molecular docking, Diffusion docking, MD simulation, MM-GBSA and meta-dynamics techniques were followed. MTT assay was performed to validate the activity of principal compound. </p><p> Results: A docking score of -6.660 and MMGBSA value of -108.008 (+/-) 9.14 kcal/mol was obtained from the investigations conducted. In addition, molecular dynamics simulation was carried out for 500 ns, yielding a stable RMSD and value of 5.6 Å, thus providing insights on the stability of the protein conformation on interaction with the principal compound. Furthermore, the <i>in vivo</i> validation studies conducted via MTT assay showed an IC₅₀ value of 73.45 (+/-) 0.45 μg /mL. </p><p> Conclusion: The research has produced encouraging findings and can be applied as a model for precise enumerations in the future. It also encourages the study of novel synthetic compounds with potential anti-cancer properties.</p>

Keywords:

NPY1R, imidazopyrazine, MM-GBSA, MTT assay, MCF-7 cell line, molecular dynamics simulation.

Affiliation:

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