Design of Novel Imidazopyrazine Derivative against Breast Cancer via Targeted NPY1R Antagonist

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. Objectives: Imidazopyrazine is a highly favored skeleton for the design of new anticancer drugs. In silico designed derivatives were screened using computer aided drug design techniques and validated using MTT assay. 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. 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 in vivo validation studies conducted via MTT assay showed an IC50 value of 73.45 (+/-) 0.45 μg /mL. 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.