Abstract

The cyclooxygenase-2 (COX-2) is an enzyme frequently overexpressed in cancer cells, making it a promising target for the preliminary screening of anticancer agents. The development of effective COX-2 inhibitors is crucial for advancing cancer therapy. This study aimed to evaluate the potential of quinazolinone derivatives as COX-2 inhibitors using in silico approaches, focusing on their structural modifications and pharmacokinetic properties. We designed and optimized 30 quinazolinone derivatives with various aromatic substituents using the DFT-B3LYP-6-31G(d,p) level of theory. Molecular docking and molecular dynamics simulations were performed to assess their binding affinity and stability within the COX-2 active site. In addition, absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions were conducted to evaluate their pharmacokinetic properties. The molecular docking results showed that benzylated quinazolinones exhibited stronger binding energies compared to phenylated ones. Specifically, methoxy (compound 5) and trifluoromethyl (compound 8) substituents at the para-position formed hydrogen bonds with key residues in the COX-2 active site. Molecular dynamics simulations confirmed the stability of these compounds during a 100 ns simulation. The molecular mechanics Poisson–Boltzmann surface area analysis indicated a higher binding energy for methoxy-substituted quinazolinones (compound 5). ADMET predictions revealed favorable pharmacokinetic properties for benzylated quinazolinones with methoxy and trifluoromethyl groups. This study highlights the potential of benzylated quinazolinones with methoxy and trifluoromethyl groups as a promising anticancer agent against COX-2.

Key words: Anticancer, COX-2, Drug Discovery, Molecular Docking, Molecular Dynamics, Pharmacokinetic properties, Quinazolinones