inhibitory potential of benzo[a]phenazin-5-ol derivatives against c-kit kinase: molecular docking and prediction of adme/drug-likeness properties

Background & objectives: c-kit, a receptor tyrosine kinase involved in intracellular signaling, has a mutated form that significantly contributes to the development of certain cancers. this study aimed to evaluate a series of benzo[a]phenazin-5-ol-tethered tri-substituted methane derivatives as potential pharmacophores for inhibiting c-kit kinase.materials & methods: benzo[a]phenazine-5-ol derivatives were sketched and converted into mol2 files using marvin software. their three dimensional (3d) structures were generated and saved in pdb format. molecular docking studies with the c-kit kinase (pdb code 1t46) were performed using autodock 4.2. additionally, the derivatives’ physicochemical properties, adme characteristics, and drug-likeness parameters were assessed with the swissadme online tool.results: molecular docking studies of benzo[a]phenazin-5-ol derivatives (a-l) against c-kit kinase revealed that compounds a and c exhibited greater selectivity and stronger inhibitory effects than the reference drug, sunitinib. ligplot analysis demonstrated that compound a formed four hydrogen bonds with arg791(a), ile789(a), and his790(a), while compound c formed two hydrogen bonds with ile571(a) and ile789(a). adme analysis indicated that all compounds, except c, d, and i, are potential p-gp substrates. drug-likeness analysis showed one or two violations of lipinski’s rule of five.conclusion: in summary, molecular docking studies identified compounds a and c as promising lead candidates for inhibiting c-kit kinase, demonstrating superior binding to the active site compared to sunitinib. adme and drug-likeness analysis revealed that compound a is a potential p-gp substrate with one violation of lipinski’s rule of five, making it the closest pharmacological match to sunitinib and a strong candidate for further investigation.