Molecular interaction between human serum albumin (HSA) and phloroglucinol derivative that shows selective anti-proliferative potential

• Published in: Journal of luminescence Vol. 192; pp. 990 - 998
• Main Authors: Mondal, Moumita, T, Pragna Lakshmi, Krishna, Ramadas, Sakthivel, Natarajan
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01-12-2017
• Subjects: Cytotoxicity; Isothermal titration calorimetry; Molecular docking; Molecular dynamics simulation; Steady-state fluorescence; Cytotoxicity; Steady-state fluorescence; Isothermal titration calorimetry; Molecular dynamics simulation; Molecular docking
• ISSN: 0022-2313; 1872-7883
• DOI: 10.1016/j.jlumin.2017.08.007

Phloroglucinol and its derivatives possess wide array of biopotentials such as antimicrobial, antioxidant, anti-inflammatory, anticancer and anti-metastatic properties. In the present investigation, for the first time, we report the anticancer potential and pharmacokinetic properties of 2,4,6-triacetylphloroglucinol (TAPG) through anti-proliferative assay and its molecular interaction with human serum albumin (HSA). HSA – TAPG interaction was explored through steady-state fluorescence, time-resolved fluorescence (TRF), circular dichroism (CD), isothermal titration calorimetry (ITC) and computational approaches. TAPG showed significant cytotoxicity towards lung, breast, colon and cervical cancer cell lines with minimal effect on normal cells. In steady-state fluorescence, the binding of TAPG strongly quenched the intrinsic fluorescence of HSA through static quenching mechanism. This explains the ground-state complex formation which was also evidenced in lifetime measurements. At different molar concentrations of TAPG, the helical content of HSA decreased and thereby influenced the secondary structural content of protein. Calculation of binding constant through fluorescence and ITC studies revealed the reversible and moderate affinity of TAPG towards HSA which allows the compound to diffuse easily from circulatory system to target tissue. Thermodynamic parameters from ITC exhibited a negative enthalpy, positive entropy and negative free energy change for HSA – TAPG interaction. This elucidates the exothermic and spontaneous reaction of binding with involvement of electrostatic interactions. Molecular docking studies showed that TAPG formed interactions with polar residues of inner and outer cluster region of site I with more affinity than site II. It was also noticeable that TAPG interactions were more stable in site I than site II during 50ns molecular dynamic simulation. Altogether, these results explain the favorable binding of TAPG with HSA which affects the drug distribution making it more bioavailable.