Antihypertensive activity of a quinoline appended chalcone derivative and its site specific binding interaction with a relevant target carrier protein

Inhibition of Angiotensin Converting Enzyme (ACE) is identified as a main therapeutic target in controlling hypertension. The principal intent of this work is to investigate the ACE inhibitory property of a quinoline appended chalcone derivative (E)-3-(anthracen-10-yl)-1-(6,8-dibromo-2-methylquinolin-3-yl)prop-2-en-1-one (ADMQ), and its binding mechanism with model transport protein BSA by employing steady state and time resolved fluorescence, Circular Dichroism (CD), in silico molecular docking, Induced Fit Docking (IFD) and Molecular Dynamics (MD) simulation. Incubation of ADMQ with kidney cortex plasma membrane shows considerable antihypertensive effect by the inhibition of ACE. ADMQ undergoes strong interaction with ACE both in the absence and presence of BSA. Comparable ACE inhibitory mechanistic profile of ADMQ with standard drug captopril has been identified in terms of the ligand interaction pattern, changes in secondary structural elements and protein RMSF. The steady state emission of BSA undergoes a remarkable decrement via ground state complex formation upon addition of ADMQ in an aqueous buffer solution of BSA at a physiological pH of 7.4 contrary to the time resolved and FRET measurement where both the static and energy transfer mechanism co-exists. The rotationally restricted ADMQ molecule shows strong binding affinity towards subdomain IIA of site I with a close proximity (2.45 nm) to the Trp 213 residue. The minor decrease of α-helical content as calculated from CD spectral measurement and 1-3 Å change in protein RMSD during MD simulation clearly indicate that the polypeptide chain is partially destabilized due to the above site specific accommodation of the host (ADMQ). A slight diminution in the ACE inhibitory profile is observed in the presence of BSA; however BSA shows lesser binding towards ADMQ in the presence of the target enzyme. The spectroscopic research described herein may provide enormously important information for ACE inhibition of the chalcone derivative and its detailed binding interaction with a carrier protein for chalcone based drug designing in medicinal chemistry research.