Molecular docking and ADMET profiling of Carbazole-rhodanine hybrid as anticancer agent

Abstract

Drug resistance and lack of specificity of currently available chemotherapeutics for cancer cells contribute to the failure of cancer chemotherapy. This highlights the pressing need to develop novel anticancer agents. This research aims to investigate the inhibiting potential of Carbazole and rhodanine derivatives against Human papillomaviruses (HPVs) and Breakpoint Cluster Region (BCR), with Abelson murine leukemia (ABL) tyrosine kinase to manage human cervical cancer and human chronic myeloid leukemia (CML), respectively. Some carbazole-rhodanine hybrids were evaluated in silico against human cervical cancer (Hela) and human CML (K562) cells. In this study, Molecular docking was used to determine binding affinity, bonding, and nonbonding interaction between the studied compounds and the target. Additionally, in-silico ADMET (adsorption, distribution, metabolism, excretion, and toxicity) screening was performed to explore the bioavailability, pharmacokinetic properties, and toxicity of the carbazole-rhodanine hybrids. The structure of the compounds was also discussed relative to their bioactivity. The molecular docking revealed that the test compounds except D, E, and L demonstrated better binding affinity, hence better inhibition efficiency towards Hela and K562 cell lines than the reference drug (etoposide). Compound G with a cyano substituent showed the highest binding affinity with the two receptors used, with a binding energy of -7.9 kcal mol^-1 against hela (6HKS) and -10.0 against K562 (5HU9). This was in accordance with the experimental result. The SAR illustrated that a strong electron-withdrawing substituent attached to the para-position of the phenyl ring increased the activity. The ADMET profiling showed that compounds E, G, and J had superior drug-likeness, pharmacokinetic, and toxicity properties. Based on the results, compound G may be a good candidate to be developed further into a therapeutic agent to treat chronic myeloid leukemia and cervical cancer.