Molecular basis of the interaction between novel isonicotinohydrazide drug derivatives with human serum albumin: Multispectroscopic and computational insights.

Isonicotinic acid hydrazide (INH), a well-known and promising first-line anti-tubercular agent, is enlisted in the World Health Organization's (WHO) list of vital medicines. Herein, the binding characteristics of more efficacious INH-derivatives with human serum albumin (HSA) were investigated using multiple spectroscopic techniques combined with molecular modelling approaches. The findings suggested that all the derivatives quench the intrinsic fluorescence of HSA via the static mode of quenching, validated by UV-visible differential spectroscopy. The stoichiometry (n) and binding constant (Kb) were calculated using the modified Stern-Volmer equation. The values manifested that IN1-C/D has comparatively higher binding affinity (Kb ̴ 104) than IN1-A/B, with 1:1 stoichiometry for all the derivatives. The corresponding thermodynamic parameters were calculated at different temperatures; the values of ∆H and ∆S reflect the Hydrogen bonds and van der Waals interactions as major molecular-forces in the binding process. The derivatives showed varied behavior towards the secondary structural conformation of HSA in CD spectroscopy. IN1-A/B/D interaction led to a decrease in α-helical content, while IN1C -HSA complexation showed an increase in α-helical content on binding. Additionally, to gain deeper molecular insights, the INH-derivatives were first analyzed using density functional theory (DFT) to optimize their structure and electronic properties, followed by molecular docking and molecular dynamics (MD) simulation with the target protein. The collective findings from these computational approaches indicate that the INH derivatives exhibit significant binding affinity towards the drug-binding site of HSA. Moreover, their intermolecular non-covalent interactions contribute to the preservation of the protein's structural stability, underscoring their potential relevance in modulating the function of the HSA protein.