Evaluation of non-covalent interactions of chlorambucil (monomer and dimer) and its interaction with biological targets: Vibrational frequency shift, electron density topological and automated docking analysis

Chlorambucil is a well-known chemotherapy drug that is being used to treat chronic myelogenous leukemia. As it contains ten flexible rotational bonds, the possible spatial conformations have been identified theoretically. The spectral signatures of monomer and dimer structures of chlorambucil and the frequency shifts due to non-covalent interactions (NCIs) have been illustrated using FT-IR and FT-Raman spectra. The bond correlation between carbon and hydrogen nuclei of chlorambucil has been obtained using 2D-HSQC NMR spectrum. The assignments of harmonic normal modes have been done in order to find the vibrational contributions of each functional group. Besides the spectroscopic studies, the electron density based quantum topological atoms in molecule analysis have been performed to explore the possible interactions between the non-bonded atoms. The reduced density gradient and isosurface plots have been used in this study to understand the strength of NCIs. The charge delocalization patterns of monomer and dimer structures were explained so as to investigate the chemical stability profile. The active sites for the electrophilic and nucleophilic attack on the monomer conformers have been determined by applying Hirshfeld charges and atomic spin densities into Fukui and Parr functions, respectively. From the automated docking analysis, it is found that chlorambucil interacts with the aldo-keto reductase family 1 (AKR1B1, AKR1B10, AKR1B15) and FAD-linked sulfhydryl oxidase ALR proteins through strong hydrogen bonds and shows a potential inhibition. In order to take into account the interactions ranging from short to long range, the modern density functionals viz. M06-2X, wB97XD, B97D which includes dispersion-corrected repulsion terms have been employed and the theoretical results were found coincide with the experimental observations. Keywords: Chlorambucil, Conformational analysis, Non-covalent interactions, FT-IR, FT-Raman, Protein-ligand interaction