Journal
MOLECULES
Volume 28, Issue 1, Pages -Publisher
MDPI
DOI: 10.3390/molecules28010089
Keywords
NUDT5; ATP synthesis; coumarin derivative; molecular dynamics simulation; metadynamics simulation; MTT assay
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Breast cancer is a heterogeneous disease and the second leading cause of cancer-related deaths among women. Plant-based derivatives and their derivatives are safer than synthetic compounds in combating chemoresistance. In this study, a template-based design of a coumarin derivative was developed to target the ADP-sugar pyrophosphatase protein. Molecular docking, molecular dynamics simulation, and metadynamics studies were performed, demonstrating the stable interaction and potential anticancer activity of the designed coumarin derivative. In vitro validation using a cytotoxicity assay confirmed its effectiveness.
Breast cancer, a heterogeneous disease, is among the most frequently diagnosed diseases and is the second leading cause of death due to cancer among women after lung cancer. Phytoactives (plant-based derivatives) and their derivatives are safer than synthetic compounds in combating chemoresistance. In the current work, a template-based design of the coumarin derivative was designed to target the ADP-sugar pyrophosphatase protein. The novel coumarin derivative (2R)-2-((S)-sec-butyl)-5-oxo-4-(2-oxochroman-4-yl)-2,5-dihydro-1H-pyrrol-3-olate was designed. Molecular docking studies provided a docking score of -6.574 kcal/mol and an MM-GBSA value of -29.15 kcal/mol. Molecular dynamics simulation studies were carried out for 500 ns, providing better insights into the interaction. An RMSD change of 2.4 angstrom proved that there was a stable interaction and that there was no conformational change induced to the receptor. Metadynamics studies were performed to calculate the unbinding energy of the principal compound with NUDT5, which was found to be -75.171 kcal/mol. In vitro validation via a cytotoxicity assay (MTT assay) of the principal compound was carried out with quercetin as a positive control in the MCF7 cell line and with an IC50 value of 55.57 (+/-) 0.7 mu g/mL. This work promoted the research of novel natural derivatives to discover their anticancer activity.
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