Studies on the interaction between HSA and new halogenated metformin derivatives: influence of lipophilic groups in the binding ability

Abstract

In the type II diabetes mellitus, Metformin hydrochloride is recommended as a common FAD approved drug. Synthesis of novel metformin series has been widely explored, mainly due to its biological importance and to improve their pharmacokinetic profile. Generally, human serum albumin (HSA) is the main protein used to study drug viability in vitro analysis. Thus, the present study reports the synthesis of three new halogenated metformin derivatives (MFCl, MFBr and MFCF₃) and its interaction toward HSA by multiple spectroscopic techniques (UV-Vis, circular dichroism, steady-state, time-resolved and synchronous fluorescence), combined to computational methods (molecular docking and quantum chemical calculation). The interaction between each halogenated metformin derivative and HSA is spontaneous (ΔG°<0), entropically driven (ΔS°>0), moderate (K_a and K_b ≈ 10⁴ M⁻¹) and occurs preferentially in the subdomain IIA (close to Trp-214 residue). Molecular docking results suggested hydrogen bonding, van der Waals and hydrophobic interactions as the main binding forces. Quantum chemical calculations suggested imino groups as the most intense electrostatic negative potentials, while the positive electrostatic potential is located at the hydrogen atoms on N,N-dimethyl and the phenyl systems which can help the hydrophobic interactions.

Communicated by Ramaswamy H. Sarma

Keywords:

• Metformin
• human serum albumin
• pharmacokinetics profile

Acknowledgements

The authors gratefully acknowledge the financial support from the Brazilian agencies: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ). Special acknowledgement is given to Prof. Nanci Camara de Lucas Garden (UFRJ) for the time-resolved and synchronous fluorescence facilities and to Prof. Carlos M. R. Sant’Anna (UFRRJ) for the computational facilities. C.H.C.S.O. acknowledges CAPES for the undergraduate fellowship, and J.C.N.-F. acknowledges INMETRO for a Visiting Professor fellowship.

Disclosure statement

No potential conflict of interest was reported by the authors.