Molecular interactions and binding dynamics of Alpelisib with serum albumins: insights from multi-spectroscopic techniques and molecular docking

Abstract

Alpelisib (ALP) is a potent anti-cancer drug showing promising activity against advanced breast cancers. Hence, profound understanding of its binding dynamics within the physiological system is vital. Herein, we have investigated interaction of ALP with human serum albumin (HSA) and bovine serum albumin (BSA) using spectroscopic techniques like absorption, fluorescence, time-resolved, synchronous and 3D-fluorescence, FRET, FT-IR, CD, and molecular docking studies. The intrinsic fluorescence of both BSA and HSA quenched significantly by ALP with an appreciable red shift in its emission maxima. Stern-Volmer analysis showed increase in K_sv with temperature indicating involvement of dynamic quenching process. This was further validated by no significant change in absorption spectrum of BSA and HSA (at 280 nm) upon ALP interaction, and by results of fluorescence time-resolved lifetime studies. ALP exhibited moderately strong binding affinity with BSA (of the order 10⁶ M⁻¹) and HSA (of the order 10⁵ M⁻¹), and the major forces accountable for stabilizing the interactions are hydrophobic forces. Competitive drug binding experiments and molecular docking suggested that ALP binds to site I in subdomain IIA of BSA and HSA. The Förster distance r was found to be less than 8 nm and 0.5 R_o < r < 1.5 R_o which suggests possible energy transfer between donors BSA/HSA and acceptor ALP. Synchronous and 3D-fluoresecnce, FT-IR and CD studies indicated that ALP induces conformational changes of BSA and HSA upon interaction.

Communicated by Ramaswamy H. Sarma

Keywords:

• Alpelisib
• serum albumins
• interaction
• dynamic quenching
• FRET
• molecular docking

Acknowledgement

We are grateful to National institute of Technology, Silchar for providing us facilities to carry out our research work. Financial assistance from DST-SERB (Project No.: ECR/2017/000441) is acknowledged for instrumentation facility. We wholeheartedly thank Dushyant Gumra and Aditi Halder, Advance Material Research Centre (AMRC), IIT Mandi, Himachal Pradesh; Dr. P. K. Sudhadevi Antharjanam, SAIF IIT Madras, Dr. Ashim Malakar, CIF IIT Guwahati for their kind co-operation always in providing us with facilities of Sophisticated analytical instruments. The first author is grateful to Dr. Abhijit Shyam (Dr. P. Mondal Laboratory, Dept. of Chemistry, Assam University) for structure optimization of the drug using Gaussian 09 software package.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

There is no funding received for the current research work.