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Spectroscopic, calorimetric and molecular docking insight into the interaction of Alzheimer’s drug donepezil with human transferrin: implications of Alzheimer’s drug

Abstract Donepezil, a highly selective and reversible inhibitor, is amongst the widely used drugs for the treatment of Alzheimer’s disease (AD) across the globe. Clinically significant human transferrin (hTf) is a key player involved in iron metabolism. The current study targets to have an insight into the interaction between donepezil and this plasma protein, hTf using UV–vis absorbance, fluorescence, isothermal titration calorimetry, circular dichroism (CD) and molecular docking techniques. UV spectroscopy of hTf in the presence of donepezil revealed the occurrence of hyperchromism coupled with blue shift in indicating complex formation. Binding constant obtained from UV–vis absorption measurements was of the order 0.9 × 104 M−1 implicative of strong binding. Fluorescence spectroscopy shows that donepezil quenches fluorescence intensity of the native hTf in dynamic manner with a shift in wavelength maxima. Donepezil binds to hTf at 310 K with a binding constant of 1.3 × 104 M−1 suggestive of strong binding. ITC results clearly suggest the reaction to be spontaneous and thermodynamically favorable. CD spectroscopy also showed a shift in the spectrum of the native hTf in the presence of donepezil suggesting formation of complex between protein and drug. Furthermore, molecular docking experiments showed Pro 91, Phe 94 and His 207 to be key players involved in the complex formation. This study gives an insight into the molecular basis of interaction between donepezil and hTf thereby aiding in understanding the activity and mechanism of protein and drug binding. This will serve as a boon for drug designing industries which are working day and night for improved treatment of existing disorders across the world. Communicated by Ramaswamy H. Sarma