In Silico Approach to Design of New Multi-Targeted Inhibitors Based on Quinoline Ring with Potential Anticancer Properties
Żaneta Czyżnikowska, Martyna Mysłek, Aleksandra Marciniak, Remigiusz Płaczek, Aleksandra Kotynia, Edward Krzyżak · International Journal of Molecular Sciences · 2025
Searching for new anticancer drugs is a significant challenge for the medical community due to the current limitations of existing treatments. The primary objective of this study was to design and optimize multi-targeted drug candidates based on a quinoline scaffold. In this paper, we adopt various in silico techniques, including molecular docking, molecular dynamics simulations, and ADMET property modeling, to predict the binding affinity and interactions of 7-ethyl-10-hydroxycamptothecin derivatives with multiple biological targets. The interactions of these compounds with three potential molecular targets, topoisomerase I, bromodomain-containing protein 4, and ATP-binding cassette sub-family G member 2 proteins, were analyzed. It has been previously proved that the inhibition of these molecular targets may have beneficial effects on cancer treatment. The designed chemical compounds can effectively interact with selected proteins, thereby establishing their potential as drug candidates. Molecular docking revealed promising binding affinities, with topoisomerase I docking scores ranging from -9.0 to -10.3 kcal/mol, BRD4 scores from -6.6 to -8.0 kcal/mol, and ABCG2 scores from -8.0 to -10.0 kcal/mol. Furthermore, the ADMET property analysis indicates promising pharmacological profiles, protein binding affinity, selectivity, and bioavailability while minimizing toxicity. For example, satisfactory logP values have been demonstrated in the favorable range for bioavailability after oral administration. Additionally, several compounds exhibited predicted aqueous solubility values greater than -3, suggesting moderate-to-good solubility, which is crucial for oral drug delivery.