A Combined Investigation with Square-Wave Voltammetry and Molecular Docking for DNA/Protein Bindings, and ADMET Studies of (E)-2,4-di-tert-butyl-6-(((4-phenoxyphenyl)imino)methyl)phenol

The binding interactions of (E)-2,4-di-tert-butyl-6-(((4-phenoxyphenyl)imino)methyl)phenol (TBIP) with bovine serum albumin (BSA), human serum albumin (HSA), and calf thymus DNA (CT-DNA) were investigated using square-wave voltammetry (SWV) at pH 7.40, as well as molecular docking (MD) application. In addition, the physicochemical properties, pharmacokinetic characteristics, toxicity potencies and biological targets of TBIP were predicted by using pkCSM and Swiss Target Prediction online tools. The ADMET properties of TBIP were compared to those of other analogue Schiff bases ((E)-1-((4-phenoxyphenylimino)methyl)naphthalen-2-ol, abbreviated as PMNO, and (E)-1-[(2-phenoxyphenylimino)methyl]naphthalen-2-ol, abbreviated as 2-PPMN). According to the SWV results, the decreased cathodic peak current of TBIP in the presence of aforementioned bio-molecules (BMs) indicated that it interacts with them. Moreover, the electrochemical results showed that BSA has a higher binding constant in the comparison to HSA and DNA, respectively, and also reveal that TBIP forms biomolecular complexes in the molar ratio of 1 : 1. On the other hand, the binding constants of TBIP to these biomolecules were also evaluated according to those of the bio-molecule (BM) complexes of PMNO, 2-PPMN, doxorubicin (Dox) and ethidium (Et+). The MD outcomes suggest that both hydrophobic and π-cation interactions were formed in the interaction between TBIP and HSA while only the hydrophobic interactions contributed to stabilizing the TBIP–BSA complex. In addition, the MD analysis of TBIP with A-DNA compound showed the binding affinity (BA) of −7.4 kcal mol−1 with two H-bonds and four π–π interactions when compared to B-DNA with BA of −7.9 kcal mol−1 and one H-bond. Finally, MD results exhibited that TBIP is a minor groove binder and H-bond interactions have paramount effect in the stabilities for its complexes with A- and B-DNA, respectively. The order in the estimated BA values of these BMs with TBIP was observed as follows: BSA>HSA>B-DNA>A-DNA. The BA values of TBIP to A- and B-DNA were compared with well-known DNA intercalators such as Dox and Et+. TBIP exhibited lower BA values than Dox, though higher than Et+. Finally, the differences observed in albumin-binding in comparison to PMNO analogue with 2-naphthol moiety appear to be mostly related to the steric effects of the tertiary butyl groups.