Molecular modeling and cytotoxic activity studies of oxirane-2-carboxylate derivatives

In this study, five 3-aryloxirane-2-carboxylate derivatives were prepared, and the antiproliferative activities of molecules were screened in lung and colon cancer cell lines. The results showed that molecules had antiproliferative activity on cancerous cells with IC₅₀ values under 100 µM. Furthermore, all of the molecules were found to have a much higher cytotoxic effect than cisplatin in colon cancer cells. The interactions of the relatively active compounds to the crucial enzyme in cancer cell proliferation, cyclin-dependent kinase 1 (CDK1), were investigated using molecular docking. The stability of the resulting CDK1-compound complexes procured from the docking was also assessed through molecular dynamics (MD) simulations. Then, the binding affinity of compounds <b>2-3a</b> and <b>2-3c</b> to the target enzyme was computed by MMPBSA. The molecular docking study demonstrated that the two most active compounds could bind to the enzyme. The binding potential of <b>2-3a</b> is anticipated to be higher as it had one more conventional hydrogen bond and a slightly lower binding energy than compound <b>2-3c</b>. The MD simulation study exhibited that the two compounds formed a stable complex with the enzyme. On the other hand, the MMPBSA energy computation implicated a slightly higher binding affinity for compound <b>2-3c</b> toward the enzyme. Furthermore, electrical and frontier molecular orbital analysis of all of the tested compounds was conducted by density functional theory (DFT) studies. Compound <b>2-3a</b> is anticipated to be the most chemically stable as it gave the highest energy gap value in the DFT analysis.