Enhanced Aggregation-Induced Delayed Electrochemiluminescence Triggered by Spatial Perturbation of Organic Dots.

Development of highly efficient, heavy-metal-free electrochemiluminescence (ECL) materials is attractive but still challenging. Herein, we report an aggregation-induced delayed ECL (AIDECL) active organic dot (OD) composed of a tert-butoxy-group-substituted benzophenone-dimethylacridine compound, which shows high ECL efficiency. The resultant ODs exhibit 2.1-fold higher ECL efficiency compared to control AIDECL-active ODs. Molecular stacking combined with theoretical calculations suggests that tert-butoxy groups effectively participate in the intermolecular interactions, further inhibiting the molecular motions in the aggregated states and thus accelerating radiative decay. On the basis of these ODs exhibiting excellent ECL performance, a proof-of-concept biosensor is constructed for the detection of miR-16 associated with Alzheimer's disease, which demonstrates excellent detection ability with the limit of detection of 1.7 fM. This work provides a new approach to improve the ECL efficiency and enriches the fundamental understanding of the structure-property relationship.

Enantioseparation of mandelic acid and substituted derivatives by high-performance liquid chromatography with hydroxypropyl-ß-cyclodextrin as chiral mobile additive and evaluation of inclusion complexes by molecular dynamics.

The enantioseparation and resolution mechanism of mandelic acid (MA), 4-methoxymandelic acid (MMA), and 4-propoxymandelic acid (PMA) were investigated by reversed-phase high-performance liquid chromatography (HPLC) with 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) as a chiral mobile-phase additive and molecular dynamics simulation. The suitable chromatographic conditions for the enantioseparation of MA, MMA, and PMA were obtained. Under the selected chromatographic conditions, these enantiomers could achieve baseline separation. The results of thermodynamic parameter analysis revealed that the main driven forces for the enantioseparation of MA, MMA, and PMA could be van der Waals forces and hydrogen-bonding interactions and the chromatographic retention of these chiral compounds was an enthalpy-driven process. The results of the molecular simulation revealed that their chiral resolution mechanism on HP-ß-CD was responsible for the formation of inclusion complexes of enantiomers with HP-ß-CD with different conformations and binding energies. And the binding energy of HP-ß-CD with (S)-isomer was larger than that with (R)-isomer, which is consistent with the experimental results of the first elution of (S)-isomer. Additionally, it is also confirmed that the interaction energies included the van der Waals energy (∆Evdw ), electrostatic energy (∆Eelec ), polar solvation energy, and SASA energy (∆Esasa ), and the separation factor (α) was closely connected with the disparity in the binding energies of optical isomers and HP-ß-CD complexes. Meanwhile, from molecular dynamics simulation, it can be found that the ∆(∆Ebinding ), (∆(∆Ebinding ) = ∆Ebinding,R - ∆Ebinding,S ) value was in order of MA-HP-ß-CD complex > MMA-HP-ß-CD complex > PMA-HP-ß-CD complex, which was consistent with the order of Δ(ΔG) values obtained from van't Hoff plot. This indicated that the molecular dynamics simulation has predictive function for chiral resolution.

Exploring the inclusion interaction of estradiol with ß-CD and HP-ß-CD with the help of molecular dynamics simulation as well as multi-spectroscopic approaches.

The inclusion behaviors of estradiol with ß-CD and HP-ß-CD were characterized using molecular dynamics simulation combined with multi-spectroscopic approaches. The findings revealed that estradiol enclosed into the cavity of ß-CD and HP-ß-CD and produced the estradiol-ß-CD and estradiol-HP-ß-CD complexes with the stoichiometry of 1:1. The association constants of the estradiol-ß-CD and estradiol-HP-ß-CD complexes were 3.14 × 104 and 3.22 × 104 M-1 at 298 K, respectively, which declined with rising temperature. The analysis results of thermodynamic parameters confirmed that the dominate interaction forces were the hydrophobic and hydrogen-bonding interactions for stabilizing the estradiol-ß-CD complex, and were the hydrogen bonding interaction and van der Waals forces for stabilizing the estradiol-HP-ß-CD complex. Moreover, it was confirmed from the results of molecular modeling that estradiol inserted into the hydrophobic cavity of ß-CD and HP-ß-CD and form a stable estradiol-CD complexes. And, it is also observed that the phenyl moiety in estradiol is almost parallel to the central axis of ß-CD and HP-ß-CD, and the phenyl moiety was located on wider rim of ß-CD and HP-ß-CD.

Investigation of binding characteristics of ritonavir with calf thymus DNA with the help of spectroscopic techniques and molecular simulation.

The binding behavior of ritonavir (RTV), a HIV/AIDS protease inhibitor, with ct-DNA was characterized through multiple testing technologies and theoretical calculation. The findings revealed that the RTV-DNA complex was formed through the noncovalent interaction mainly including conventional hydrogen bonds and carbon hydrogen bonds as well as hydrophobic interactions (pi-alkyl interactions). The stoichiometry and binding constant of the RTV-DNA complex were 1:1 and 1.87 × 103 M-1 at 298 K, respectively, indicating that RTV has moderate affinity with ct-DNA. The findings confirmed that RTV binds to the minor groove of DNA. The outcomes of CD experiments showed that the binding with RTV changed the conformation of DNA slightly. However, the conformation of RTV had obvious changes after binding to DNA, meaning that the flexibility of RTV molecule played an important role in stabilizing the RTV-DNA complex. Meanwhile, the results of DFT calculation revealed that the RTV and DNA interaction caused the changes in the frontier molecular orbitals, dipole moment and atomic charge distribution of RTV, altering the chemical properties of RTV when it bound to DNA. Communicated by Ramaswamy H. Sarma.

Evaluation of the interaction of novel tyrosine kinase inhibitor apatinib mesylate with bovine serum albumin using spectroscopies and theoretical calculation approaches.

Apatinib mesylate (APM), a novel tyrosine kinase inhibitor, has been applied in treating various cancers. In the present study, the binding mechanism of APM with bovine serum albumin (BSA) was studied by making use of various spectroscopic and theoretical calculation approaches to provide theoretical support for further studying its pharmacokinetics and metabolism. The results from fluorescence experiments showed that the quenching mechanism of BSA induced by APM was static quenching and the APM-BSA complex with the stoichiometry of 1:1 was formed during binding reaction. Moreover, the findings also showed that the binding process of APM to BSA was spontaneous and enthalpy-driven, and the mainly driving forces were hydrogen bonding, van der Waals as well as hydrophobic interactions. From the outcomes of the competitive experiments, it can be found that the binding site was primarily nestled in sub-domain IIIA of BSA (site II) which was in line with the results of molecular docking. An appreciable decline in α-helix content of BSA can be observed from the FT-IR data, meaning that the conformational change of BSA occurred after binding with APM, this phenomenon can be corroborated by the results of UV-vis, synchronous fluorescence and 3D fluorescence studies. Furthermore, the effect of some metal ions (e.g. K+, Co2+, Ni2+, Fe3+) on the binding constant of APM to BSA was explored.Communicated by Ramaswamy H. Sarma.

Insight into the binding behavior of ceritinib on human α-1 acid glycoprotein: Multi-spectroscopic and molecular modeling approaches.

Ceritinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor for mainly treating non-small cell lung cancer (NSCLC). This investigation focused on to clarify in detail the binding behavior between human α-1 acid glycoprotein (HAG) and ceritinib by means of multi-spectroscopic and molecular modeling approaches. Fluorescence data obtained at four different temperatures indicated ceritinib quenched the endogenous fluorescence of HAG by a static quenching mechanism. Based on the Kb value at 105 M-1 level, it can be inferred that the binding affinity between both is strong. From findings of thermodynamic parameter analysis, the competitive experiments with ANS and sucrose as well as molecular dynamic (MD) simulation, it can be inferred that hydrophobicity, hydrogen bonding, van der Waals forces as well as electrostatic interactions exist in the binding interaction between ceritinib and HAG. The findings from UV absorption, circular dichroism, and synchronous fluorescence spectroscopy indicated that the change in the microenvironment around the protein structure, secondary structure and tryptophan residues occurred after interaction with ceritinib. The data from FRET analysis confirmed that the non-radiative energy transfer between the two existed and the binding distance between the acceptor (ceritinib) and donor (HAG) was 2.11 nm. Meantime, the influence of Ca2+, Cu2+, Ni2+, Co2+, and Zn2+ ions on the binding interaction of ceritinib with HAG were obvious, especially Zn2+ ion.

Assessment on the binding affinity between ritonavir with model transport protein: a combined multi-spectroscopic approaches with computer simulation.

The binding affinity between ritonavir (RTV) and model transport protein, BSA was assessed through multi-spectroscopic approaches and computer simulation. The findings revealed RTV statically quenched the fluorescence of BSA and formed the 1:1 RTV-BSA complex with the binding constant (Kb) of 1.06 × 103 ∼ 5.08 × 103 M-1 under the studied temperatures (298 ∼ 310 K). During the interaction of RTV with BSA, the hydrogen bonds and van der Waals forces acted as predominant function while the hydrophobicity played an assistant function. Molecular modeling further verified the result obtained from the competitive binding experiments, RTV preferentially fit into in the sub-domain IIIA of BSA. The perturbation in the secondary structures of BSA upon acting with RTV was observed from IR results, whereas synchronous and 3D fluorescence spectral findings unraveled the slight change in the hydrophobicity surrounding Tyr and Trp residues.Communicated by Ramaswamy H. Sarma.

Assessment on the binding characteristics of dasatinib, a tyrosine kinase inhibitor to calf thymus DNA: insights from multi-spectroscopic methodologies and molecular docking as well as DFT calculation.

The binding characteristics of calf thymus DNA (ct-DNA) with dasatinib (DSTN), a tyrosine kinase inhibitor was assessed through multi-spectroscopic methodologies and viscosity measurement combined with molecular docking as well as DFT calculation to understand the binding mechanism, affinity of DSTN onto ct-DNA, effect of DSTN on ct-DNA conformation, and among others. The results confirmed DSTN bound onto ct-DNA, leading to forming the DSTN-ct-DNA complex with the binding constant of 4.82 × 103 M-1 at 310 K. DSTN preferentially inserted to the minor groove of ct-DNA with rich A-T region, that was the binding mode of DSTN onto ct-DNA was groove binding. The enthalpic change (ΔH0) and entropic change (ΔS0) during the binding process of DSTN with ct-DNA were 128.9 kJ mol-1 and 489.2 J mol-1 K-1, respectively, confirming clearly that the association of DSTN with ct-DNA was an endothermic process and the dominative driven-force was hydrophobic interaction. Meanwhile, the results also indicated that there was a certain extent of electrostatic force and hydrogen bonding, but they maybe play an auxiliary role. The CD measurement results confirmed the alteration in the helical configuration of ct-DNA but almost no change in the base stacking after binding DSTN. The results revealed that there was the obvious change in the conformation, the dipole moment, and the atomic charge distribution of DSTN in the B-DNA complexes, compared with free DSTN, to satisfy the conformational adaptation. From the obtained fronitier molecular orbitals of DSTN, it can be inferred that the nature of DSTN alters with the change of the environment around DSTN. Communicated by Ramaswamy H. Sarma.

Insights on the interaction mechanism of brigatinib to human α-1-acid glycoprotein: Experimental and computational approaches.

Brigatinib, a multi-target kinase inhibitor, is primarily used to treat anaplastic lymphoma kinase (ALK)-positive patients with advanced non-small cell lung cancer (NSCLC) who have previously received crizotinib or are resistant to crizotinib. In this study, we focused on elucidating the interaction mechanism between brigatinib and human alpha-1-acid glycoprotein (HAG) through experimental and computational approaches. Steady-state fluorescence and UV-vis spectroscopy measurements revealed that brigatinib could quench the intrinsic fluorescence of HAG in a static quenching manner and formed the brigatinib-HAG complex with the stoichiometric ratio of 1:1. The findings revealed that brigatinib had a stronger affinity on HAG due to higher binding constant of 2.91 × 105 M-1 at 298 K. It can be proved from thermodynamic parameter analysis that brigatinib spontaneously bound to HAG in the means of enthalpy driven, the main forces for stabilizing brigatinib-HAG complexes were hydrogen bonding and hydrophobic interactions. The experimental results also indicated that the binding interaction induced micro-environmental changes around tryptophan residues and the alteration in secondary structure of HAG. The presence of metal ions like Mg2+, Zn2+, Ca2+, Ni2+ and Co2+ affects the binding interaction and thus change the therapeutic efficacy of brigatinib. Molecular docking results suggested that brigatinib was embedded to the hydrophobic cavity of HAG. The experimental and computational results certified that hydrogen bonding and hydrophobic interaction as well as electrostatic energy and van der Waals forces plays a leading role in the binding process.