2. Academic Validation
  3. Unraveling the molecular interaction of Larotrectinib with calf thymus DNA: A comprehensive study using multi-spectroscopic, thermodynamic, and computational techniques

Unraveling the molecular interaction of Larotrectinib with calf thymus DNA: A comprehensive study using multi-spectroscopic, thermodynamic, and computational techniques

  • Biophys Chem. 2025 Dec:327:107512. doi: 10.1016/j.bpc.2025.107512.
Manal A Alossaimi 1,  Taibah Aldakhil 2,  Heba Elmansi 3,  Fathalla Belal 3,  Galal Magdy 4
Affiliations

Affiliations

  • 1 Pharmaceutical Chemistry Department, College of Pharmacy, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia. Electronic address: m.alossaimi@psau.edu.sa.
  • 2 Pharmaceutical Chemistry Department, College of Pharmacy, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.
  • 3 Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
  • 4 Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33511, Egypt; Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Mansoura National University, Gamasa 7731168, Egypt. Electronic address: galal_magdy@pharm.kfs.edu.eg.
PMID: 40816098 DOI: 10.1016/j.bpc.2025.107512
Abstract

The study of the interaction between small molecules and biological macromolecules is a critical area of research with significant implications across various scientific fields. Larotrectinib, a tropomyosin kinase inhibitor, is used to treat patients with solid tumors harboring neurotrophic tyrosine receptor kinase (NTRK) gene fusions. In this investigation, the interaction between larotrectinib and calf thymus DNA (ctDNA) was thoroughly examined using a combination of techniques, including UV-Vis spectrophotometry, spectrofluorimetry, viscosity measurements, ionic strength variation, thermodynamic analysis, molecular dynamics simulations, and docking studies. The results demonstrated a strong binding interaction between larotrectinib and ctDNA, with the drug primarily binding to the minor groove of ctDNA. This binding mode was established through competitive binding assays using ethidium bromide and rhodamine B, as well as UV-Vis spectroscopy and viscosity analysis. The binding constant (Kb) at 298 K, determined using the Benesi-Hildebrand equation, was found to be 4.4 × 105 M-1, pointing out a high binding affinity between larotrectinib and ctDNA. Thermodynamic analysis revealed that the interaction is driven mainly by hydrophobic forces and hydrogen bonding, as evidenced by the calculated enthalpy (ΔH0) and entropy (ΔS0) changes. Molecular docking studies further supported these findings, showing that larotrectinib binds preferentially to the AT-rich regions of the B-DNA minor groove. This was validated by molecular dynamics studies, which provided additional confirmation of the binding mechanism. Overall, these findings provide valuable understanding into the molecular interactions and pharmacological mechanisms of larotrectinib, contributing to a deeper insight of its role as a potent Anticancer agent.

Keywords

Binding interaction; DNA; Larotrectinib; Molecular modeling; Spectroscopy; Thermodynamic.

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