Π Inter-actions Research Articles

In situ surface-enhanced infrared spectroscopy study of adenine-thymine co-adsorption on gold electrodes as a function of the pH

In situ attenuated total reflection surface enhanced infrared absorption spectroscopy (ATR-SEIRAS) has been used to study the co-adsorption of adenine and thymine on gold nanostructured electrodes from D2O and H2O solutions at acid, neutral and basic pH values.The comparison between the ATR-SEIRA band when adenine (A) and thymine (T) are co-adsorbed and the corresponding bands of both bases adsorbed individually has revealed the existence of interactions between the complementary bases at the gold-electrolyte interface, at acid, neutral and basic pH values. The most significant bands of adsorbed adenine undergo an enhancement in the presence of thymine. This can be explained if adenine adopts an orientation with the molecular plane more normal to the electrode surface and, at least at neutral pH, the surface concentrations of adenine increases in the presence of thymine. In the presence of adenine, the characteristic absorption bands of adsorbed thymine nearly disappear at potentials of the chemisorption region of thymine, suggesting the orientation of thymine molecular plane from normal to nearly parallel relative to the electrode surface, after the addition of adenine.The comparison of the spectral regions at 2900–3800cm−1 of adsorbed adenine in H2O solutions in the absence and in the presence of thymine only reveals the enhancement mentioned above. The bands corresponding to the NH2 stretching modes of adenine do not undergo any significant frequency shift, which permit us to discard the participation of adsorbed adenine in hydrogen bonding interactions (A-T) of the Watson-Crick or of the Hoogsteen types.Cooperative interactions including pi interactions A-T of the “edge to face” type and coplanar hydrogen bonding T-T are proposed to be responsible of the long range organization of the adlayer formed by the coadsorbed bases.

Exploration of the molecular interactions between angiotensin-I-converting enzyme (ACE) and the inhibitory peptides derived from hazelnut (Corylus heterophylla Fisch.)

The mechanism of action of food-derived angiotensin-I-converting enzyme (ACE) inhibitory peptides has not been completely elucidated. In the present study, ion-exchange chromatography, gel filtration chromatography, reverse phase-high performance liquid chromatography, and liquid chromatography-electrospray ionization–tandem mass (LC-ESI-MS/MS) were employed for purifying and identifying the ACE inhibitory peptides from hazelnut. To understand the mode of action of these peptides, ACE inhibition kinetics, in vitro and in vivo bioavailability assays, active site analysis, and interaction between the inhibitory peptides and ACE were investigated. The results identified novel ACE inhibitory peptides Ala-Val-Lys-Val-Leu (AVKVL), Tyr-Leu-Val-Arg (YLVR), and Thr-Leu-Val-Gly-Arg (TLVGR) with IC50 values of 73.06, 15.42, and 249.3 μM, respectively. All peptides inhibited the ACE activity via a non-competitive mode. The binding free energies of AVKVL, YLVR, and TLVGR for ACE were −3.46, −6.48, and −7.37 kcal/mol, respectively. The strong inhibition of ACE by YLVR may be attributed to the formation of cation–pi interactions.

Arsenic-phosphorus interactions in the soil-plant-microbe system: Dynamics of uptake, suppression and toxicity to plants.

High arsenic (As) concentrations in the soil, water and plant systems can pose a direct health risk to humans and ecosystems. Phosphate (Pi) ions strongly influence As availability in soil, its uptake and toxicity to plants. Better understanding of As(V)-Pi interactions in soils and plants will facilitate a potential remediation strategy for As contaminated soils, reducing As uptake by crop plants and toxicity to human populations via manipulation of soil Pi content. However, the As(V)-Pi interactions in soil-plant systems are complex, leading to contradictory findings among different studies. Therefore, this review investigates the role of soil type, soil properties, minerals, Pi levels in soil and plant, Pi transporters, mycorrhizal association and microbial activities on As-Pi interactions in soils and hydroponics, and uptake by plants, elucidate the key mechanisms, identify key knowledge gaps and recommend new research directions. Although Pi suppresses As uptake by plants in hydroponic systems, in soils it could either increase or decrease As availability and toxicity to plants depending on the soil types, properties and charge characteristics. In soil, As(V) availability is typically increased by the addition of Pi. At the root surface, the Pi transport system has high affinity for Pi over As(V). However, Pi concentration in plant influences the As transport from roots to shoots. Mycorrhizal association may reduce As uptake via a physiological shift to the mycorrhizal uptake pathway, which has a greater affinity for Pi over As(V) than the root epidermal uptake pathway.

Deciphering structural stability and binding mechanisms of potential antagonists with smoothened protein

Identification of new potential inhibitors against Hedgehog pathway activator protein Smoothened (SMO) is considered to be of higher importance to improvise the future cancer therapeutics. Different SMO inhibitors/drugs (e.g. Cyclopamine, Vismodegib, Taladegib) used till date are found to be associated with several drug-related resistivity and toxicity. To explore the ability of new drug/inhibitor molecules, which can show better/similar binding and dynamic stability as compared to known inhibitors, virtual screening against SMO is performed followed by the comparative docking and molecular dynamic studies. ‘ZINC12368305’ is found to be the best molecule among the entire data-set, as it shows the highest binding affinity and stable conformations. Here, an integrative approach using Dynamic Graph Theory is introduced to gain the molecular insights of the structural integrity of these protein complexes at the residue level by analyzing the corresponding Protein Contact Networks along the Molecular Dynamics trajectories. The study further focuses to understand the detailed binding mechanisms of available inhibitor/drug molecules along with the newly predicted molecule. It is observed that a unique big cluster of low fluctuating residues at the vicinity of the drug binding pocket of the SMO in ZINC12368305-bound complex is present and driving it toward a more stable region. A close inspection on this site reveals the presence of a stable Pi–Pi interaction between the pyrazole group-associated phenanthrene ring of ZINC12368305 and aromatic ring of Phe484 of SMO, which could be the potential factor of ZINC12368305 to create a more stable complex with SMO as compared to the other inhibitors.

Extended chiral Khuri\u2013Treiman formalism for eta rightarrow 3pi and the role of the a_0(980), f_0(980) resonances

Recent experiments on eta rightarrow 3pi decays have provided an extremely precise knowledge of the amplitudes across the Dalitz region which represent stringent constraints on theoretical descriptions. We reconsider an approach in which the low-energy chiral expansion is assumed to be optimally convergent in an unphysical region surrounding the Adler zero, and the amplitude in the physical region is uniquely deduced by an analyticity-based extrapolation using the Khuri–Treiman dispersive formalism. We present an extension of the usual formalism which implements the leading inelastic effects from the Kbar{K} channel in the final-state pi pi interaction as well as in the initial-state eta pi interaction. The constructed amplitude has an enlarged region of validity and accounts in a realistic way for the influence of the two light scalar resonances f_0(980) and a_0(980) in the dispersive integrals. It is shown that the effect of these resonances in the low-energy region of the eta rightarrow 3pi decay is not negligible, in particular for the 3pi ^0 mode, and improves the description of the energy variation across the Dalitz plot. Some remarks are made on the scale dependence and the value of the double quark mass ratio Q.

Ligand-binding characterization of simulated β-adrenergic-like octopamine receptor in Schistocerca gregaria via progressive structure simulation

It is important to design insecticides having both low drug resistance and less undesirable toxicity for desert locust control. Specific GPCRs of Schistocerca gregaria, especially β-adrenergic-like octopamine receptor (SgOctβR), can be considered as its potential effective insecticide targets. However, either the unavailability of SgOctβR’s structure or the inadequate capability of its sequence lead the development of insecticide for Schistocerca gregaria meets its plateau. To relax this difficulty, this paper develops a promising progressive structure simulation from SgOctβR’s sequence, to its predicted structure of SgOctβR in vacuum, to its conformation as well as its complex with endogenous ligand octopamine in a solvent-membrane system. The combined approach of multiple sequence alignment, static structural characterization, and dynamic process of conformational change during binding octopamine reveal three important aspects. The first one is the characterization of SgOctβR’s active pocket, including the attending secondary structure elements, its hydrophobic residues and nonpolar surface. The second one is the interaction with octopamine, especially the involved hydrogen bonds and an aromatic stacking of pi–pi interactions. The third one is the potential binding sites, including six highly conserved residues and one highly variable residue for locust insecticide design. This work is definitely helpful for the further structure-based drug design for efficient and eco-friendly insecticides, as well as site-directed mutagenesis biochemical research of SgOctβR.

In silico identification of novel antagonists and binding insights by structural and functional analyses of guanylate kinase of Leishmania donovani and interaction with inhibitors

Guanylate kinase (GK; EC 2.7.4.8) is an important enzyme which catalyzed the ATP-dependent phosphorylation of GMP (guanosine monophosphate) into GDP (guanosine diphosphate) for survival of parasites; this suggests that it is a good target for design inhibitor(s). Knowledge of 3D structure of GKLdv is essential for elucidating interaction studies with the inhibitors and compared with substrate binding pattern in both the built model and template structures. The final reliable model of GKLdv has revealed α/β type protein with a G-X2-G-X-G-K that has a catalytic conserved domain in both template and model structure. The core domain consists of a central five-stranded parallel β-sheet (β5, β6, β3 and β4) whereas model has both α1-α10 and β1-β9 and active sites consist of flexible loop (FL1 to FL3). The superimposition structure of main-chain atoms of the GK model with closely homologue of GK (1EX7, chain A), has revealed better alignment and its root mean square deviation (RMSD) (43% similarity) is 0.602Ǻ. The virtual screening result has suggested that the binding pocket interacts with 5GP (5′-guanylic acid) with exhibited higher score in both GOLD and LigandFit scores and involve in amino acid interaction (H-bonding) are Arg40, Try80, Tyr52, Ser36, Glu71, and Asp102. The reported antileishmanial diospyrin (IC₅₀-7.2μM) has also exhibited higher binding activities (Dock score - 49.314 and Fitness score - 52.69) with frequently involved amino acids are Arg45, Glu102, Tyr35, Tyr54, Ser38, Tyr82, Ile103, Asp104, Lys106, Lys18, Pro13 and Ser14. The sigma pi interaction between Ile103 with diospyrin ring has revealed greater stable complex after molecular dynamic simulation studies. The best scoring compounds need for further validation in-vitro test.

Reliable computational design of biological-inorganic materials to the large nanometer scale using Interface-FF

The function of nanomaterials and biomaterials greatly depends on understanding nanoscale recognition mechanisms, crystal growth and surface reactions. The Interface Force Field (IFF) and surface model database are the first collection of transferable parameters for inorganic and organic compounds that can be universally applied to all materials. IFF uses common energy expressions and achieves best accuracy among classical force fields due to rigorous validation of structural and energetic properties of all compounds in comparison to perpetually valid experimental data. This paper summarises key aspects of parameterisation, including atomic charges and transferability of parameters and current coverage. Examples of biomolecular recognition at metal and mineral interfaces, surface reactions of alloys, as well as new models for graphitic materials and pi-conjugated molecules are described. For several metal–organic interfaces, a match in accuracy of computed binding energies between of IFF and DFT results is demonstrated at ten million times lower computational cost. Predictive simulations of biomolecular recognition of peptides on phosphate and silicate surfaces are described as a function of pH. The use of IFF for reactive molecular dynamics is illustrated for the oxidation of Mo3Si alloys at high temperature, showing the development of specific porous silica protective layers. The introduction of virtual pi electrons in graphite and pi-conjugated molecules enables improvements in property predictions by orders of magnitude. The inclusion of such molecule-internal polarity in IFF can reproduce cation–pi interactions, pi-stacking in graphite, DNA bases, organic semiconductors and the dynamics of aqueous and biological interfaces for the first time.

Synthesis, crystal structure, Hirshfeld surface studies and frontier orbitals analysis of 4-(1-benzofuran-2-yl)-2-methyl-6-phenylpyrimidine

Abstract 4-(benzofuran-2-yl)-2-methyl-6-phenylpyrimidine (BFMPP) has been synthesized and characterized by FT-IR, 1H &13CNMR and Mass spectrometry techniques. Single crystals of title compound were grown by slow evaporation solution growth technique at room temperature and crystal structure has been determined by single crystal X-ray diffraction technique. The title compound (BFMPP) crystallizes in monoclinic space group P21, with cell dimensions a = 4.803(3) A, b = 9.498(5) A, c = 15.557(9) A, β = 93.25 (4)o and Z = 2. The crystal structure is stabilized by weak C H…N intermolecular interactions generating a one dimensional C(4) network propagating along the [1 0 0] direction and two pi…pi interactions. Further, a detailed analysis of the Hirshfeld surfaces facilitating an understanding of the type and nature of intermolecular interactions in the supramolecular structure is made. The calculated HOMO-LUMO energy gap discloses that charge transfer occurs within the molecule.

Effect of angiotensin I-converting enzyme (ACE) inhibition and nitric oxide (NO) production of 6,6′-bieckol, a marine algal polyphenol and its anti-hypertensive effect in spontaneously hypertensive rats

Abstract In the present study, the effects of 6,6′-bieckol isolated from Ecklonia cava on angiotensin I-converting enzyme (ACE) inhibition and nitric oxide (NO) production, and the inhibitor’s binding modes using the crystal structure of ACE were examined. The effects of 6,6′-bieckol on systolic blood pressure (SBP) after meals were also investigated. We predicted the 3D structure of ACE and used a docking algorithm to understand the binding between ACE and 6,6′-bieckol. The molecular docking study revealed that ACE inhibitory activity of 6,6′-bieckol was mainly attributed to the hydrogen bond interactions (Lys454, His353, Glu162, Glu376, Glu384 and Glu411) and Pi interactions (Lys511 and His513) between ACE and 6,6′-bieckol. 6,6′-bieckol significantly increased the production of nitric oxide (NO) and by phosphorylating endothelial nitric oxide synthase (eNOS) in human endothelial cells. Furthermore, antihypertensive effect in spontaneously hypertensive rats (SHRs) also revealed that oral administration of the compound can down-regulate (28.6 mmHg in 6 h) systolic blood pressure (SBP).

Sandwiches of N-doped diamondoids and benzenevialone pair–cation and cation–pi interaction: a DFT study

Cation–lone pair and cation–pi interactions in the complexes of N-doped dimondoids.

Purification and molecular docking study of angiotensin I-converting enzyme (ACE) inhibitory peptides from hydrolysates of marine sponge Stylotella aurantium

Abstract Angioteinsin I-converting enzyme (ACE) inhibitory peptide was isolated from marine sponge (Stylotella aurantium) hydrolysate prepared by various hydrolysis enzymes. The peptic hydrolysate exhibited highest ACE inhibitory activity among them and was fractionated into three ranges of molecular weight. The below 5 kDa fraction showed the highest ACE inhibitory activity and was used for subsequent purification steps. The amino acid sequences of the purified peptides were identified to be Tyr-Arg (337.2 Da), and Ile-Arg (287.2 Da). The purified peptides from marine sponge had an IC50 value of 237.2 μM and 306.4 μM, respectively. The molecular docking study revealed that ACE inhibitory activity of the purified peptides was mainly attributed to the hydrogen bond interactions and Pi interaction between the dipeptides and ACE. The results suggest that marine sponge, S. aurantium would be an attractive raw material for the manufacture of anti-hypertensive nutraceutical ingredients.

Fluorometric estimation of amino acids interaction with colloidal suspension of FITC functionalized graphene oxide nanoparticles

A hydrosol approach developed to synthesize fluorescence quenched fluorescein isothiocyanate (FITC) functionalized colloidal suspension of graphene oxide nanoparticles (GONP). UV–vis spectroscopic measurements showed characteristic peak at 236nm and 300nm due to pi–pi* interaction in CC and n-pi* transition in CO bond of GONP, respectively. Attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectra showed reduced intensity of 1429cm−1 IR band of GONP due to the electrostatic and pi–pi interactions of FITC with GONP in FITC-GONP. ATR-FTIR spectra of different amino acid co-functionalised FITC-GONP showed an increase in the FTIR band intensity at 1429cm−1 which was significantly reduced due to electrostatic/pi–pi interactions of FITC with GONP in the absence of the amino acids. A peak at 1084cm−1 in ATR-FTIR spectra appears which confirms the interaction between amine group of amino acids and COO− groups at GONP surface. The FITC interaction with GONP lead to fluorescence resonance energy transfers (FRET) and resulted in a liner decrease in the FITC fluorescence with an increase of GONP concentration. An increase in the reappearance of FITC fluorescence observed while the amino acid concentration was increased in co-functionalised FITC-GONP. The quantified amount of reappeared fluorescence of FITC in amino acid co-functionalised FITC-GONP depends on the concentration, polar and non-polar nature of amino acids. The reappearance of FITC from the surface of FITC-GONP with the addition of amino acid was found to be consistent with the organic substitute, size of amino acids and their functionalities. Therefore, FRET based method using FITC-GONP colloidal suspension may have potential application in determining the binding nature of biomolecules with GONP for biomedical applications.

Structure and chemical reactivity of lithium-doped graphene on hydrogen-saturated silicon carbide

Herein, we studied the structure and hydrogenation of graphene supported on hydrogen-terminated SiC, with intercalated Li atoms. Strong nonbonded interactions occur between graphene and the Si–H groups. The latter were found to be significantly augmented by the intercalation of Li atoms, which enhanced the SiH::pi interactions. Although the electronic structure of graphene did not experience significant changes when supported on hydrogen-terminated SiC, a small gap of 0.04 eV was computed at the HSEH1PBE/6-31G* level. The clustering of Li atoms over graphene was prevented by the SiC support. A significant enhancement of reactivity could be corroborated due to the presence of intercalated Li atoms, given that the C–H binding energy was increased by almost 1 eV with respect to pristine graphene. We expect that hydrogen-terminated SiC with intercalated Li atoms can be used to enhance the chemical reactivity of graphene, given that it strongly interacts with graphene but does not compete for the electrons donated by Li.

The Inosine Monophosphate Dehydrogenase, GuaB2, Is a Vulnerable New Bactericidal Drug Target for Tuberculosis.

VCC234718, a molecule with growth inhibitory activity against Mycobacterium tuberculosis (Mtb), was identified by phenotypic screening of a 15344-compound library. Sequencing of a VCC234718-resistant mutant identified a Y487C substitution in the inosine monophosphate dehydrogenase, GuaB2, which was subsequently validated to be the primary molecular target of VCC234718 in Mtb. VCC234718 inhibits Mtb GuaB2 with a Ki of 100 nM and is uncompetitive with respect to IMP and NAD+. This compound binds at the NAD+ site, after IMP has bound, and makes direct interactions with IMP; therefore, the inhibitor is by definition uncompetitive. VCC234718 forms strong pi interactions with the Y487 residue side chain from the adjacent protomer in the tetramer, explaining the resistance-conferring mutation. In addition to sensitizing Mtb to VCC234718, depletion of GuaB2 was bactericidal in Mtb in vitro and in macrophages. When supplied at a high concentration (≥125 μM), guanine alleviated the toxicity of VCC234718 treatment or GuaB2 depletion via purine salvage. However, transcriptional silencing of guaB2 prevented Mtb from establishing an infection in mice, confirming that Mtb has limited access to guanine in this animal model. Together, these data provide compelling validation of GuaB2 as a new tuberculosis drug target.

Chlorination by-products of bisphenol A enhanced retinoid X receptor disrupting effects

There is increasing evidence of activities of chlorinated by-products of bisphenol A (BPA) on retinoic acid system. Their agonistic and antagonistic activities to human retinoid X receptor (RXR) were assessed by a two-hybrid yeast assay. Aqueous solutions of 1mg/L BPA were chlorinated by sodium hypochlorite (NaClO). It showed that chlorination of BPA increased RXRβ antagonistic activity, while no agonistic activity was detected, showing chlorine might act as a toxic potentiator rather than a toxic deactivator in RXRβ disrupting effects. BPA and its byproducts including 2,2′,6,6′-tetrachlorobisphenol A (TCBPA) and 2,4,6-trichlorophenol (TCP) were quantitatively determined by gas chromatography/mass spectrometry (GC/MS). BPA rapidly degraded. With the increasing of ICC and reaction time, concentration of formed TCBPA increased initially then decreased, while concentration of formed TCP increased stably. Using the toxic equivalent (TEQ) approach, the main contributors should be mono-, di- and tri- chlorobisphenol A at initial chlorine concentration (ICC) of 1mg/L. At ICC of 2 and 5mg/L, the main contributors were TCBPA and TCP, being 57.7%–70.7% and 45.3%–59.4%. Molecular docking showed BPA chlorination by-products might have the same mode of action with BPA, forming hydrogen bond and pi–pi interaction with their OH group or hydrophobic ring.

Inhibitory activity evaluation and mechanistic studies of tetracyclic oxindole derivatives as α-glucosidase inhibitors

α-Glucosidase inhibitors are known to prevent the digestion of carbohydrates and reduce the impact of carbohydrates on blood glucose. Three series of tetracyclic oxindole derivatives were designed, synthesized and evaluated for α-glucosidase inhibitory activity in vitro. Compound 6t exhibited the most potent inhibitory activity with IC50 0.7 μM and was about 170 times as active as acarbose (IC50 = 115.8 μM). The kinetic analysis of compound 6t revealed it inhibited α-glucosidase in an irreversible and mixed manner. Fluorescence spectra indicated that 6t directly bound to α-glucosidase. Docking simulation showed the existence of potential H-bonding, van der Waals, Pi and Sigma-Pi interactions between 6t and α-glucosidase.

RGG boxes within the TET/FET family of RNA-binding proteins are functionally distinct

ABSTRACTThe multi-functional TET (TAF15/EWS/TLS) or FET (FUS/EWS/TLS) protein family of higher organisms harbor a transcriptional-activation domain (EAD) and an RNA-binding domain (RBD). The transcriptional activation function is, however, only revealed in oncogenic TET-fusion proteins because in native TET proteins it is auto-repressed by RGG-boxes within the TET RBD. Auto-repression is suggested to involve direct cation–pi interactions between multiple Arg residues within RGG boxes and EAD aromatics. Via analysis of TET transcriptional activity in different organisms, we report herein that repression is not autonomous but instead requires additional trans-acting factors. This finding is not supportive of a proposed model whereby repression occurs via a simple intramolecular EAD/RGG-box interaction. We also show that RGG-boxes present within reiterated YGGDRGG repeats that are unique to TAF15, are defective for repression due to the conserved Asp residue. Thus, RGG boxes within TET proteins can be functionally distinguished. While our results show that YGGDRGG repeats are not involved in TAF15 auto-repression, their remarkable number and conservation strongly suggest that they may confer specialized properties to TAF15 and thus contribute to functional differentiation within the TET/FET protein family.

The Involvement of OsPHO1;1 in the Regulation of Iron Transport Through Integration of Phosphate and Zinc Deficiency Signaling.

Plants survival depends on their ability to cope with multiple nutrient stresses that often occur simultaneously, such as the limited availability of essential elements inorganic phosphate (Pi), zinc (Zn), and iron (Fe). Previous research has provided information on the genes involved in efforts by plants to maintain homeostasis when a single nutrient (Pi, Zn, or Fe) is depleted. Recent findings on nutritional stress suggest that plant growth capacity is influenced by a complex tripartite interaction between Pi, Zn, and Fe homeostasis. However, despite its importance, how plants integrate multiple nutritional stimuli into complex developmental programs, and which genes are involved in this tripartite (Pi ZnFe) interaction is still not clear. The aim of this study was to examine the physiological and molecular responses of rice (Oriza sativa L.) to a combination of Pi, Zn, and/or Fe deficiency stress conditions. Results showed that Fe deficiency had the most drastic single-nutrient effect on biomass, while the Zn deficiency-effect depended on the presence of Pi in the medium. Interestingly, the observed negative effect of Fe starvation was alleviated by concomitant Pi or PiZn depletion. Members of the OsPHO1 family showed a differential transcriptional regulation in response PiZnFe combinatory stress conditions. Particularly, the transcripts of the OsPHO1;1 sense and its natural antisense cis-NatPHO1;1 showed the highest accumulation under PiZn deficiency. In this condition, the Ospho1;1 mutants showed over-accumulation of Fe in roots compared to wild type plants. These data reveal coordination between pathways involved in Fe transport and PiZn signaling in rice which involves the OsPHO1; 1, and support the hypothesis of a genetic basis for Pi, Zn, and Fe signaling interactions in plants.

Isocryptotanshinone, a STAT3 inhibitor, induces apoptosis and pro-death autophagy in A549 lung cancer cells

Signal transducer and activator of transcription 3 (STAT3) is a potential drug target for chemotherapy. Cryptotanshinone (CTS) was identified as a potent STAT3 inhibitor, while the effect of other tanshinones remains unknown. In this study, the influence of eight tanshinones on STAT3 activity was initially screened and isocryptotanshinone (ICTS) significantly inhibited STAT3 activity in a dual luciferase assay. ICTS inhibited the constitutive and inducible phosphorylation of STAT3 at Y705 without affecting the phosphorylation of STAT3 at S727 in A549 lung cancer cells. Furthermore, ICTS inhibited the nuclear translocation of STAT3. Compared with CTS, ICTS exhibited a stronger inhibitory effect on STAT3 phosphorylation and on A549 cytotoxicity. ICTS induced autophagy as evidenced by the accumulation of autophagic vacuoles and the increased expression of LC3 protein and autophagosomes. ICTS-induced cell death was partially reversed by the autophagy inhibitor chloroquine. The docking assay predicted that both ICTS and CTS bind the SH2 domain of STAT3. ICTS formed hydrogen bonds and pi–pi interaction with the nearby amino acid residues of Lys591, Arg609, and Ser636. These findings suggested that ICTS, a natural compound, is a potent STAT3 inhibitor. ICTS induced apoptosis and pro-death autophagy in A549 cells.