Comparative Binding Analysis by Computational Methods and Quartz Crystal Microbalance: Case of hnRNPA2B1 Protein and
Olga Volkova1, Anastasia Serova1, Viacheslav Kravtsov1
1Infochemistry Scientific Center, ITMO University, Saint Petersburg 191002, Russia.
Abstract:
Irinotecan (IRT) is a well-established anticancer drug that primarily targets topoisomerase 1. This study reveals a direct interaction between IRT and heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1), which is a protein implicated in the progression of different kinds of cancers. The Quartz Crystal Microbalance (QCM) was applied to measure a binding affinity between IRT and hnRNPA2B1, resulting in an apparent binding constant KD_QCM of (15 ± 1) × 10-3, which is comparable to the apparent binding constant KD_QCM of (17 ± 2) × 10-3 for the reference ligand camptothecin. Further computational analysis via molecular docking and molecular dynamics (MD) simulations demonstrated stable binding of IRT to the RNA recognition domain (RRM) of hnRNPA2B1, yielding a binding free energy ΔG of -10.36 kcal·mol-1. These findings suggest that IRT may exert an inhibitory effect on hnRNPA2B1, potentially contributing to its anticancer activity beyond topoisomerase 1 inhibition.
Insights
Irinotecan (IRT), a cancer drug, directly interacts with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1), a protein linked to cancer progression. This interaction suggests a new mechanism for IRT
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Irinotecan (IRT) is a key chemotherapy agent targeting topoisomerase 1.
- Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) is increasingly recognized for its role in cancer development.
- The precise molecular interactions of IRT beyond topoisomerase 1 inhibition are not fully elucidated.
Purpose of the Study:
- To investigate the direct binding interaction between Irinotecan (IRT) and heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1).
- To characterize the binding affinity and stability of the IRT-hnRNPA2B1 complex.
- To explore potential novel anticancer mechanisms of IRT.
Main Methods:
- Quartz Crystal Microbalance (QCM) was employed to quantify the binding affinity between IRT and hnRNPA2B1.
- Molecular docking simulations were performed to predict the binding mode and site.
- Molecular dynamics (MD) simulations were utilized to assess the stability of the complex.
Main Results:
- QCM analysis revealed a significant binding affinity between IRT and hnRNPA2B1 (KD_QCM = (15 ± 1) × 10-3), comparable to camptothecin.
- Molecular docking and MD simulations confirmed stable binding of IRT to the RNA recognition domain (RRD) of hnRNPA2B1.
- A binding free energy (ΔG) of -10.36 kcal·mol-1 was calculated, indicating favorable binding.
Conclusions:
- Irinotecan (IRT) directly binds to heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1).
- This interaction occurs within the RNA recognition domain of hnRNPA2B1.
- The findings suggest that IRT may inhibit hnRNPA2B1, offering a potential new mechanism for its anticancer effects beyond topoisomerase 1 inhibition.
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