Unraveling the binding mechanism of olanzapine with human serum transferrin: a multispectroscopic and computational investigation.

Abstract

The interaction between olanzapine (OLZ) and human serum transferrin (Tf), both in the absence and presence of Fe³⁺, was analyzed using multispectroscopic methods, molecular docking, and molecular dynamics simulations under physiological conditions. Spectroscopic results confirmed OLZ's strong affinity for Tf, driven by static interactions complemented by minor dynamic effects. The values of the binding constants, K_a (2.48 × 10⁸, 4.73 × 10⁷_, 1.13 × 10⁷ at 296, 303 and 310 K, respectively) indicate that OLZ-Tf complex is more stable at lower temperatures. Negative thermodynamic parameter values (enthalpy, ΔH⁰ = -168.46 kJmol^-1; entropy, ΔS⁰ = -408.63 JK^-1 mol^-1; and free energy, ΔG⁰ = -47.50 kJmol^-1) suggest an exothermic and spontaneous binding process dominated by hydrogen bonding and van der Waals forces. Structural changes in Tf upon OLZ binding confirmed by spectroscopic measurements. Results of molecular docking revealed that OLZ exhibits a stronger binding affinity for apotransferrin (Fe³⁺-free Tf) than for holo-transferrin (iron-bound Tf), with preferential interaction in the N-lobe. The effect of Fe³⁺ on OLZ-Tf interactions was examined, confirming that iron modulates the binding mechanism. Molecular dynamics (MD) simulations supported these findings, showing OLZ stabilizes Tf's structure while maintaining its flexibility for transport. These results suggest that OLZ can bind to Tf and influence OLZ's bioavailability and pharmacokinetics, offering potential implications for drug design and clinical applications in altered iron homeostasis.