In vitro investigation of the binding characteristics of dacomitinib to human α 1-acid glycoprotein: Multispectral and computational modeling.

Dacomitinib is a highly selective second-generation tyrosine kinase inhibitor that can irreversibly bind to tyrosine kinase and is mainly used in the treatment of lung cancer. The binding characteristics of dacomitinib with human α 1-acid glycoprotein (HAG) were analyzed by multispectral and computational simulation techniques. The fluorescence spectra showed that dacomitinib can quench the fluorescence of HAG by forming the HAG-dacomitinib complex with a molar ratio of 1:1 (static quenching). At the temperature similar to that of the human body, the affinity of dacomitinib to HAG (8.95 × 106 M-1) was much greater than that to BSA (3.39 × 104 M-1), indicating that dacomitinib will give priority to binding onto HAG. Thermodynamics parameters analysis and driving force competition experiments showed that hydrogen bonding and hydrophobic forces were the major sources for keeping the complex of HAG-dacomitinib stable. The experimental outcomes also showed that the binding of dacomitinib can lead to the loosening of the skeleton structure of HAG, which led to a slight change in the secondary structure, and also reduces the hydrophobicity of the microenvironment of Trp and Tyr residues. The binding sites of dacomitinib on HAG and the contribution of key amino acid residues to the binding reaction were determined by molecular docking and molecular dynamics (MD) simulation. In addition, it was found that there was a synergistic effect between dacomitinib and Mg2+ and Co2+ ions. Mg2+ and Co2+ could increase the Kb of dacomitinib to HAG and prolong the half-life of dacomitinib.

Insight into intermolecular binding mechanism of apatinib mesylate and human alpha-1-acid glycoprotein: combined multi-spectroscopic approaches with in silico.

Apatinib mesylate (APM), an oral tyrosine kinase inhibitor, has a good anti-tumor activity in the treatment of various cancers, particularly in advanced non-small cell lung cancer. In this study, the intermolecular binding mechanism between APM and human alpha-1-acid glycoprotein (HAG) was investigated by combining multi-spectroscopic approaches with in silico techniques. The findings revealed that APM gave rise to the fluorescence quenching of HAG by forming a ground-state complex between APM and HAG with a stoichiometric ratio of 1:1, and APM has a moderate affinity for HAG as the binding constant of APM and HAG of approximately 105 M-1, which was larger than the APM-HAG complex. The findings from thermodynamic parameter analysis indicated that the dominant driving forces for the formation of the APM-HAG complex were van der Waals forces, hydrogen bonding and hydrophobic interactions, which were also verified with site-probe studies and molecular docking. The findings from in silico study indicated that APM inserted into the opening of the hydrophobic cavity of HAG, leads to a slight conformational change in the HAG, which was verified by circular dichroism (CD) measurements, that was, the beta sheet level of HAG decreased. Additionally, the results of synchronous and 3D fluorescence spectroscopies confirmed the decline in hydrophobicity of the microenvironment around Trp and Tyr residues. Moreover, some common metal ions such as Cu2+, Mg2+, Fe3+, Ca2+, and Zn2+ could cause the alteration in the binding constant of APM with HAG, leading to the change in the efficacy of APM. It will be expected that these study findings are to provide useful information for further understanding pharmacokinetic and structural modifications of APM.Communicated by Ramaswamy H. Sarma.

Comprehending the intermolecular interaction of dacomitinib with bovine serum albumin: experimental and theoretical approaches.

Dacomitinib (DAC), as a member of tyrosine kinase inhibitors is primarily used to treat non-small cell lung cancer. The intermolecular interaction between DAC and bovine serum albumin (BSA) was comprehended with the help of experiments and theoretical simulations. The outcomes indicated that DAC quenched the endogenous fluorescence of BSA through static quenching mode. In the binding process, DAC was preferentially inserted into the hydrophobic cavity of BSA subdomain IA (site III), and a fluorescence-free DAC-BSA complex with molar ratio of 1:1 was generated. The outcomes confirmed that DAC had a stronger affinity on BSA and the non-radiative energy transfer occurred in the combination process of two. And, it can be inferred from the outcomes of thermodynamic parameters and competition experiments with 8-aniline-1-naphthalenesulfonic acid (ANS) and D-(+)- sucrose that hydrogen bonds (H-bonds), van der Waals forces (vdW) and hydrophobic forces had a significant impact in inserting DAC into the hydrophobic cavity of BSA. The outcomes from multi-spectroscopic measurements that DAC could affect the secondary structure of BSA, that was, α-helix content decreased slightly from 51.0% to 49.7%. Moreover, the combination of DAC and BSA led to a reduction in the hydrophobicity of the microenvironment around tyrosine (Tyr) residues in BSA while had little influence on the microenvironment of around tryptophan (Trp) residues. The outcomes from molecular docking and molecular dynamics (MD) simulation further demonstrated the insertion of DAC into site III of BSA and hydrogen energy and van der Waals energy were the dominant energy of DAC-BSA stability. In addition, the influence of metal ions (Fe3+, Cu2+, Co2+, etc.) on the affinity of the system was explored.Communicated by Ramaswamy H. Sarma.

Exploring the binding behaviors between nisoldipine and bovine serum albumin as a model protein by the aid of multi-spectroscopic approaches and in silico.

Bovine serum albumin (BSA), a model protein was used to evaluate the binding behavior of nisoldipine and human serum albumin by a series of experiments and in silico in this article. The outcomes suggested that nisoldipine and BSA formed the nisoldipine-BSA complex with a molar ratio of 1:1, caused the fluorescence quenching of BSA, which quenching mechanism was attributable to static quenching. The binding constant of the nisoldipine-BSA complex was (1.3-3.0) × 104 M-1 at 298-310 K, indicating that nisoldipine on BSA protein had a moderate affinity. During the complexation of nisoldipine with BSA, nisoldipine can spontaneously insert into the site II (subdomain III A) of BSA and the distance of energy transfer from donor group in protein to acceptor group in nisoldipine was 3.21 nm, which led to the change in the hydrophobicity of the microenvironment surrounding Trp residues and in the secondary structure of BSA. Additionally, the findings also confirmed that the hydrogen bond and van der Waals force were responsible for forming the nisoldipine-BSA complex and the complexation process was a spontaneous exothermic process.Communicated by Ramaswamy H. Sarma.

Investigation on the binding behavior of human α1-acid glycoprotein with Janus Kinase inhibitor baricitinib: Multi-spectroscopic and molecular simulation methodologies.

Baricitinib is a Janus Kinase (JAK) inhibitor that is primarily used to treat moderately to severely active rheumatoid arthritis in adults and has recently been reported for the treatment of patients with severe COVID-19. This paper describes the investigation of the binding behavior of baricitinib to human α1-acid glycoprotein (HAG) employing a variety of spectroscopic techniques, molecular docking and dynamics simulations. Baricitinib can quench the fluorescence from amino acids in HAG through a mix of dynamic and static quenching, according to steady-state fluorescence and UV spectra observations, but it is mainly static quenching at low concentration. The binding constant (Kb) of baricitinib to HAG at 298 K was at the level of 104 M-1, indicating a moderate affinity of baricitinib to HAG. Hydrogen bonding and hydrophobic interactions conducted the main effect, according to thermodynamic characteristics, competition studies between ANS and sucrose, and molecular dynamics simulations. For the change in HAG conformation, the results of multiple spectra showed that baricitinib was able to alter the secondary structure of HAG as well as increase the polarity of the microenvironment around the Trp amino acid. Furthermore, the binding behavior of baricitinib to HAG was investigated by molecular docking and molecular dynamics simulations, which validated experimental results. Also explored is the influence of K+, Co2+, Ni2+, Ca2+, Fe3+, Zn2+, Mg2+ and Cu2+plasma on binding affinity.

Exploring the binding characteristics of bovine serum albumin with tyrosine kinase inhibitor entrectinib: Multi-spectral analysis and theoretical calculation.

Entrectinib (ENB) is one of multi-target tyrosine kinase inhibitors, which is mainly used for treating neurotrophic tyrosine receptor kinase gene fusion positive solid tumors. The binding characteristics of ENB and bovine serum albumin (BSA) were studied by experiments and theoretical calculations. The steady-state fluorescence showed that ENB quenched the fluorescence of BSA through mixed quenching, and ENB was dominated by static quenching at low concentration. ENB and BSA had a moderate affinity, formed a complex with a stoichiometric ratio of 1:1 and the binding constant of about 105 M-1 at 298 K, and Förster non-radiative energy transfer occurs. According to the driving force competition experiment, thermodynamic parameter analysis and theoretical calculation, hydrogen bond, van der Waals force and hydrophobic force were the main factors affecting the stability of the ENB-BSA complex. Molecular docking and site markers competition showed that ENB spontaneously bound to the Site III of BSA so that ENB could make the skeleton of BSA loose, the spatial structure of BSA changed (α-helix decreased by 3.1%, random coil increased by 1.7%), and the microenvironment of Tyr and Trp residues changed. The existence of Co2+ metal ions can enhance the binding effect, thus prolonging the half-life of ENB in vivo, which may improve the efficacy of ENB, while Ca2+, Cu2+ and Mg2+ metal ions will reduce the efficacy of ENB.

Elucidation of the interaction mechanism of olmutinib with human α-1 acid glycoprotein: insights from spectroscopic and molecular modeling studies.

Olmutinib, the third-generation tyrosine kinase inhibitor, is applied in treating non-small cell lung cancer (NSCLC). The aim of this study is to elucidate the interaction mechanism of olmutinib with human α-1 acid glycoprotein (HAG), an important carrier protein, by mean of multi-spectroscopic and molecular simulation techniques. Fluorescence spectral results confirmed that the fluorescence of this carrier protein can be quenched by olmutinib in the static quenching mode, and this anticancer drug possesses a moderate binding affinity on HAG. The evidence from thermodynamic analysis, replacement interaction with ANS and sucrose, and computational simulation results showed that hydrogen bonding, hydrophobic interactions, and van der Waals forces involved the olmutinib-HAG complexation process. The results from UV-vis, 3D fluorescence and synchronous fluorescence spectroscopy proved that binding anticancer drug olmutinib caused the alteration in the microenvironment around Trp residues. And, circular dichroism spectral results provided the support for the conformational alterations in the carrier protein. The data also proved that olmutinib preferably bound to the hydrophobic cavity of HAG and the binding distance between the two was 2.21 nm. In addition, it can be found that the presence of some metal ions such as Zn2+, Ca2+, Ni2+ and Cu2+ would exert a certain extent effect on the olmutinib-HAG complexation process.Communicated by Ramaswamy H. Sarma.

Assessment on binding characteristics of ethiprole and a model protein bovine serum albumin (BSA) through various spectroscopic techniques integrated with computer simulation.

To investigate the binding characteristics of pesticide ethiprole (ETP) with serum albumin is of great significance for pathological analysis of pesticide poisoning, gene mutation, and clinical detection. In present work, the binding characteristics of ETP with a model protein BSA has been estimated by means of multi-spectroscopic approaches integrated with computer simulation. The outcomes testified that the intrinsic fluorescence of BSA was mainly quenched by ETP in a static quenching mode and the stable ETP-BSA complex with the stoichiometry of 1:1 and the binding constant of 6.81 × 103 M-1 (298 K) was produced. The outcomes revealed that ETP combined preferentially to the subdomain IIA (Site I) of BSA and caused the decline in the content of α-helix of BSA and the enhancement in the hydrophobicity of environment centered on Trp residues. The outcomes of experimental and theoretical studies provide the sufficient evidence about the driving forces for the complexation of ETP with BSA, which included van der Waals forces (vdW), hydrogen bonding (H-bonding) interaction, and hydrophobicity. Simultaneously, the theoretical calculation results also confirmed the existence of the significant changes in the physicochemical natures of ETP including molecular conformation, dipole moment, frontier orbital energy, and the atomic charge distribution, which was a responsible for the complexation with BSA.Communicated by Ramaswamy H. Sarma.

Comprehending binding features between ibrutinib and Human Alpha-1 acid glycoprotein: Combined experimental approaches and theoretical simulations.

Human alpha-1 acidic glycoprotein (HAG) is one of the proteins widely present in the blood, and the level of HAG in patients with cancer and inflammation is significantly increased. As one of transport proteins in the blood, the ability of HAG to bind with a drug, especially alkaline drugs, affects significantly the drug content at the target site, which in turn affects the efficacy of the drug. In this study, the interaction mechanism between HAG and the first generation Bruton's tyrosine kinase (BTK) inhibitor namely ibrutinib was explored by a combination of multi-spectroscopic techniques and theoretical calculations. The findings revealed that the quenching and binding constants of the HAG-ibrutinib system both reduced as the temperature rose, demonstrating that ibrutinib quenched the intrinsic fluorescence of HAG in a static manner. It was confirmed that HAG and ibrutinib formed a 1:1 complex with moderate affinity due to the binding constant of around 105 M-1 and accompanied by Förster resonance energy transfer. It was verified by thermodynamic parameter analysis and competition assays as well as molecular simulation that the existence of hydrogen bonds, van der Waals forces, and hydrophobic forces in the complexation of HAG and ibrutinib.The findings from theoretical calculations including molecular docking and theoretical calculation simulation confirmed that ibrutinib bound to the barrel hydrophobic pocket of HAG with a binding energy of -41.9 kJ∙mol-1, and the the binding constant of around 105 M-1 and the contribution of each residue in the complexation of ibrutinib and HAG. Additionally, it can be confirmed that metal ions affected the binding interaction of ibrutinib with HAG, among them, some promoted binding while others inhibited it.

Exploring the binding characteristics of febuxostat, an inhibitor of xanthine oxidase with calf thymus DNA: Multi-spectroscopic methodologies and molecular docking.

In this paper, the interacting characteristics of febuxostat (FBST), an inhibitor of xanthine oxidase for treating gout patients with hyperuricemia with calf thymus DNA (ctDNA) was investigated through multi-spectroscopic methodologies combined with theoretical calculation for understanding the interacting mode on ctDNA, affinity with ctDNA, interacting forces, as well as the alteration in the conformation of ctDNA after interacting FBST The experimental results demonstrated that interacting FBST with ctDNA formed 1:1 complex, the association constant was 913 M-1 at 298 K, suggesting the affinity of FBST on ctDNA was very weak, the interacting mode of FBST on ctDNA was groove binding, and it inserted into the minor groove with rich A-T region of ctDNA. Based on the results of the thermodynamic analysis and theoretical calculation, it can be inferred that the dominated interacting forces between FBST and ctDNA were van der Waals forces and hydrogen bond. And, interacting FBST with ctDNA was a spontaneous, enthalpy-driven, and exothermic process because of ΔG0 < 0, ΔH0 < 0, and |ΔH0| > T|ΔS0|. The results of the circular dichroism (CD) measurements indicated the conformation of ctDNA was weakly disturbed after interacting with FBST but still maintained B-conform. The studied results offer significant insight into further clarifying whether it has genotoxicity.

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.

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.

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.

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.

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.

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.