Inhibitory Potential of Benzo[a]phenazin-۵-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-۵-ol-tethered tri-substituted methane derivatives as potential pharmacophores for inhibiting C-Kit kinase. Materials & Methods: Benzo[a]phenazine-۵-ol derivatives were sketched and converted into Mol۲ files using Marvin software. Their three dimensional (۳D) structures were generated and saved in PDB format. Molecular docking studies with the C-Kit kinase (PDB code ۱t۴۶) were performed using AutoDock ۴.۲. 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-۵-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 Arg۷۹۱(A), Ile۷۸۹(A), and His۷۹۰(A), while compound C formed two hydrogen bonds with Ile۵۷۱(A) and Ile۷۸۹(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.

کلیدواژه ها:

benzo[a]phenazin-۵-ol ، molecular docking ، C-Kit kinase ، Auto Dock ۴.۲ ، drug-likeness