Spectroscopic and computational study of molecular interaction of Pexidartinib with homologous mammalian transport proteins

• The molecular mechanism of interaction between Pexidartinib and mammalian serum albumins is governed by static quenching. • The binding locus is site II’ in the interface between subdomain IIA and IIB of the serum albumins. • The interaction involves an interplay of hydrogen bonding and hydrophobic interactions in stabilising the binding. • PEX binds more effectively with human serum albumin. Binding of biologically important molecules with plasma proteins highly influence its availability, distribution, and metabolism, and thus has great significance in determining its therapeutic efficiency. Hence, studying its interaction with plasma proteins is prime and inevitable. Herein, we have investigated the molecular interaction of Pexidartinib, a novel, primitive and highly selective therapeutical agent against CSF-1R overexpression, with human serum albumin (HSA) and bovine serum albumin (BSA) using various spectroscopic methods, docking and simulations. The intrinsic fluorescence of the proteins considerably quenched on PEX addition accompanied by a slight blue shift. The complex formation between PEX and BSA/HSA induced some alterations in the molecular milieu of the tryptophan residues. The active binding locus was found to be within the hydrophobic cavity of Sudlow site I of both BSA and HSA. The binding dynamics suggest the interplay of hydrogen bonding and hydrophobic interactions in complex stabilisation. MD simulations provides valuable insights into the dynamic facets of the molecular recognition processes involved and governs the stability factor of protein post ligand complexation.