RESUMEN
Since the last decade, hybrid drug strategies have attracted many researchers for their improved anti-cancer potential incomparison to single drug components. Complying to this approach, 28 novel Uracil–Coumarin hybrids with differentsized linkers (2–5 carbon atoms) and substituents were designed to occupy the active site of protein epidermal growthfactor receptor (EGFR) tyrosine kinase (Protein Data Bank ID: 1M17). Molecular docking studies were performedfor all ligands (A1-D7) to identify the potential candidate using Schrödinger software. The relative binding affinity ofhybrids toward EGFR was compared with standard Erlotinib on the basis of gScore and Emodel score. Positively, allthe hybrids docked inside the cavity and showed significant interactions, compounds A6, A2, and A7 with short-chainlinker (two carbon atoms) and halogen substituents were found to have more interactions and better docking score thanstandard Erlotinib. The visualization results depicted that compound A6 showed the highest affinity and formed thebest binding pose to the target EGFR with gScore = −8.891 kcal/mol and Emodel score = −100.744 in comparison tostandard Erlotinib (gScore of −8.538 kcal/mol and Emodel score = −80.588). Moreover, a molecular dynamics studyalso reveals that ligand A6 forms a stable complex with root mean square deviation (RMSD) of 0.3 nm and the plateauphase started just after 10 ns (time). Hence, the present research provides computational insights of Uracil–Coumarinhybrids as potential ligands against EGFR tyrosine kinase and in future in vitro investigations of these hybrids mayprove their therapeutic potential against cancer.
RESUMEN
Cancer is the most dreadful disease and the second main cause of death worldwide. The continuous developments havebeen going on in order to design potent molecules such that this leading cause of death can be dealt with. In order todecrease the level of toxicity and to improve the selectivity of drugs toward cancer targets, the development of hybridmolecules has become the center of research, and scientists are doing timeless efforts to generate such a hybrid whichhas got no comparison with the previous developments. The heterocyclic moiety Uracil and many of its derivativeswere already exposed as promising anticancer agents. Moreover, coupling of Uracil and 5-Fluorouracil (5-FU) withdifferent pharmacophores has been proven to be an excellent strategy against cancer. Hence, the present review is aneffort to collectively represent all the earlier and recent developments of Uracil and 5-FU hybrids reported to have asignificant anticancer profile. Expectantly, we can assure that this article can serve as the basis for further developmentsin Uracil and 5-FU hybrids and will surely motivate the medicinal chemists for producing unique anticancer drug