Study of the binding interaction of salmon sperm DNA with nintedanib, a tyrosine kinase inhibitor using multi-spectroscopic, thermodynamic, and in silico approaches

Abstract

The study of the intermolecular binding interaction of small molecules with DNA can guide the rational drug design with greater efficacy and improved or more selective activity. In the current study, nintedanib's binding interaction with salmon sperm DNA (ssDNA) was thoroughly investigated using UV-vis spectrophotometry, spectrofluorimetry, ionic strength measurements, viscosity measurements, thermodynamics, molecular docking, and molecular dynamic simulation techniques under physiologically simulated conditions (pH 7.4). The obtained experimental results showed that nintedanib and ssDNA had an apparent binding interaction. Nintedanib's binding constant (<i>K_b</i>) with ssDNA, as determined using the Benesi-Hildebrand plot, was 7.9 × 10⁴ M^-1 at 298 K, indicating a moderate binding affinity. The primary binding contact forces were hydrophobic and hydrogen bonding interactions, as verified by the enthalpy and entropy changes (<i>ΔH⁰</i> and <i>ΔS⁰</i>), which were - 16.25 kJ.mol^-1 and 39.30 J mol^-1 K^-1, respectively. According to the results of UV-vis spectrophotometry, viscosity assays, and competitive binding interactions with ethidium bromide or rhodamine B, the binding mode of nintedanib to ssDNA was minor groove. Molecular docking and molecular dynamic simulation studies showed that nintedanib fitted into the B-DNA minor groove's AT-rich region with high stability. This study can contribute to further understanding of nintedanib's molecular mechanisms and pharmacological effects.