Inhibitory Potential of Benzo[a]phenazin-5-ol Derivatives Against C-Kit Kinase: Molecular Docking and Prediction of ADME/Drug-Likeness Properties

Abolfazl  Olyaei; Monir  Shalbafan; Fatemeh  Rahimi; Mahdieh  Sadeghpour

doi:10.18502/jabs.v14i3.16359

Abolfazl Olyaei Department of Chemistry, Faculty of Science, Imam Khomeini International University, Qazvin, Iran
Monir Shalbafan Department of Chemistry, Faculty of Science, Imam Khomeini International University, Qazvin, Iran
Fatemeh Rahimi Department of Chemistry, Faculty of Science, Imam Khomeini International University, Qazvin, Iran
Mahdieh Sadeghpour Department of Chemistry, Qazvin Branch, Islamic Azad University, Qazvin, Iran

DOI: https://doi.org/10.18502/jabs.v14i3.16359

Keywords: benzo[a]phenazin-5-ol, molecular docking, C-Kit kinase, Auto Dock 4.2, drug-likeness

Abstract

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.