Effect of electric field on the microcosmic properties of cation compound containing 2,2,6,6-tetramethyl-1-piperidinyloxy and imidazole unit.

A theoretical study of the electric-field effect on the electronic structures and related properties of the cation compound containing 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and imidazole unit has been carried out, using the density functional theory (DFT) at the (U) B3LYP/6-31+G(d,p) level. The changes and regularities of geometric and electronic properties of the researched compound under electric field were revealed in detail. The results show the following: (1) Electric field has a very important effect on the orbital energy, dipole moment, natural population, and structure of the cation compound. Most of these properties are changed orderly with the increase of the electric-field intensity. (2) It is very interesting to find that in the present different electric-field intensities, the structure of cation compound after getting an electron becomes bis-radical form, that is, no mater in or out of electric-field, the cation compound will exist in a triplet state after getting an electron. (3) When getting an electron, the change of the cation structure mainly appears on the imizadole head, and when losing an electron, the change mainly appears on the TEMPO head. These theoretical results considering the electric-field effect for the cation compound help to explain the related experimental phenomena and further to direct the functional molecular design of this kind of compound.

Exploration of the binding mode between (-)-zampanolide and tubulin using docking and molecular dynamics simulation.

The binding mode of (-)-zampanolide (ZMP) to tubulin was investigated using docking, molecular dynamics (MD) simulation, and binding free-energy calculations. The docking studies validated the experimental results indicating that the paclitaxel site is the binding site for (-)-ZMP. The 18 ns MD simulation shows the docking mode has changed a lot, whereas it offers more reliable binding data. MM-PBSA binding free-energy calculations further confirmed the results of the MD simulation. The study revealed that hydrophobic interactions play an important role in stabilizing the binding, and the strong hydrogen bond formed with Asp224 enhances the affinity for tubulin. Meanwhile, the results support the assumption that (-)-ZMP can be attacked by His227, leading to a nucleophilic reaction and covalent binding. These theoretical results lead to a greater understanding of the mechanism of action of binding to tubulin, and will therefore aid the design of new compounds with higher affinities for tubulin.

Docking and molecular dynamics studies of the binding between Peloruside A and tubulin.

The molecular docking, MD simulation and binding free energy calculation were performed to explore the probable binding modes between PLA and tubulin. Through docking study, three possible binding sites for PLA were speculated as follows: the taxane site, the alternative site and a new site in α-tubulin. Then, 12.0 ns MD simulations show that these binding modes predicted by docking have been changed more or less, whereas the MD simulations offer more reliable binding details. The MM-PBSA binding free-energy calculations reasonably identify that the taxane site is the most favorable binding site of PLA and the alternative site is the secondary one, which can be used to explain some experimental facts. These studies theoretically resolve the priority of binding sites for PLA and offer the reliable binding modes between PLA and tubulin, and thus help to understanding the action mechanism for this kind of inhibitor.

Theoretical studies on DNA-photocleavage efficiencies of Ru(II) polypyridyl complexes.

Theoretical studies on the DNA-photocleavage efficiencies of Ru(II) polypyridyl complexes 1-4 have been carried out using density functional theory (DFT). First, an evaluation of the computational accuracy of the redox potentials for [Ru(bpy)(3)](2+) in the ground state and the excited state was tested by different computational methods. Secondly, the redox potentials of complexes 1-4 in the excited state were accurately computed. Finally, the trend in the DNA-photocleavage efficiencies (φ) of complexes 1-4, i.e., φ(4) > φ(3) > φ(2) > φ(1), were reasonably explained by the excited-state reduction potentials and the electron-transfer activation energies. In particular, the DNA-photocleavage efficiencies of two new Ru(II) complexes 3 and 4 were predicted.

Theoretical studies on DNA-photocleavage efficiencies and mechanisms of Ru(II) polypyridyl complexes.

Theoretical studies on the DNA-photocleavage efficiencies and mechanisms of Ru(II) complexes [Ru(bpy)(2)(L)](2+) (bpy = 2,2'-bipyridine; L: dppz = dipyrido[3,2-a:2',3'-c]phenazine; mitatp = 5-methoxy-isatino[1,2-b]-1,4,8,9-tetraazatriphenylene; nitatp = 5-nitro-isatino [1,2-b]-1,4,8,9-tetraazatriphenylene) 1-3 were carried out using density functional theory (DFT). First, the accuracies of redox potentials computed for [Ru(bpy)(3)](2+) in the ground state and the excited state by different computational methods were tested, and then the redox potentials of complexes 1-3 in their excited states were computed accurately. Secondly, the trend in the DNA-photocleavage efficiencies (ϕ) of complexes 1-3 [i.e., ϕ(2) > ϕ(3) > ϕ(1)] was reasonably well explained by their excited-state reduction potentials and their electron-transfer activation energies. Finally, the photoinduced oxidation-reduction mechanism utilized by these complexes was explored, and the DNA-photocleavage process was explained rationally.

Theoretical studies of QSAR and molecular design on a novel series of ethynyl-3-quinolinecarbonitriles as SRC inhibitors.

A theoretical study on the two-dimensional, three-dimensional quantitative structure-activity relationships and docking analysis of a novel series of ethynyl-3-quinolinecarbonitriles acting as Src inhibitors has been carried out. To correlate the c-Src kinase-inhibition activity of these compounds with the two-dimensional and three-dimensional structural properties for 39 known compounds, some excellent quantitative structure-activity relationships models with satisfying internal and external predictive abilities were established. A combined method of the density functional theory, molecular mechanics and statistics as well as the comparative molecular field analysis was applied to develop two-dimensional- and three-dimensional-quantitative structure-activity relationship models. The leave-one-out cross-validation q² values of two-dimensional-quantitative structure-activity relationship and comparative molecular field analysis models are 0.834 and 0.812, respectively. The predictive abilities of these models were further validated by the test set including 10 compounds, and the predicted IC50 values were in a good agreement with the experimental ones. The appropriate binding orientations and conformations of these compounds interacting with c-Src kinase were also revealed by the docking study. Based on two-dimensional- and three-dimensional-quantitative structure-activity relationship results along with docking analysis, some important factors responsible for inhibitory activity of this series of compounds were discussed in detail. These factors can be summarized as follows: selecting certain large-size substituent R2, increasing the negative charge of the first atom of substituent R1 and the net charge of the C15 atom on ring-C will enhance the activity. Meanwhile, the interaction information between protein and ligand was also revealed in detail. These results help to understand the action mechanism and designing novel potential Src inhibitors. Based on the established models and some designing considerations, three new compounds with rather high predicted Src-inhibitory activity have been theoretically designed and presented to experimenters for reference.

Theoretical studies on the related properties of Co(III) polypyridyl complexes interacting with DNA.

Theoretical studies on the related properties of Co(III) polypyridyl complexes [Co(phen)(2)L](3+) (L: dppz = dipyrido[3,2-a:2',3'-c]phenazine; phen = 1,10-phenanthroline; dione = 1,10-phenanthroline-5,6-diketone) 1-3 interacting with DNA, including the DNA-binding, DNA-photocleavage and spectral properties, have been carried out. First, the full geometry-optimizations of these three complexes in their ground states were carried out in aqueous solution. The optimized structures of these three complexes were docked into DNA-base-pairs using the Dock6.0 program. Secondly, the binding modes of complexes 1-3 were revealed in detail and the trend in DNA-binding affinities was reasonably explained. Thirdly, the electronic absorption and emission spectra of docking model of the optimal complex 1 were calculated and simulated. The experimental intense absorption and emission bands of Co(Ш) complex 1 in the presence of DNA were explained in detail, in particular, the reason why the emission spectra of complex 1 in the presence of DNA are greatly stronger than those in the absence of DNA was theoretically elucidated. Finally, the DNA-photocleavage essential of complexes was explored and the DNA photocleavage efficiencies (φ), i.e., φ(1)>φ(2)>φ(3), was also reasonably explained.

Theoretical studies on pyrimidine substituent derivatives as dual inhibitors of AP-1 and NF-kappaB.

Theoretical studies on the three-dimensional (3D) quantitative structure-activity relationship (QSAR) and mechanisms of action of a series of pyrimidine substituent derivatives as dual inhibitors of AP-1 and NF-kappaB were carried out using comparative molecular field analysis (CoMFA) and docking methods. The established 3D-QSAR model exhibits a satisfying statistical quality and prediction ability. Docking results show somewhat lower average values of the flexible and rigid energy scores in the chosen binding sites. The docking analysis offers appropriate orientations and conformations of these compounds at the binding sites to both AP-1 and NF-kappaB in good agreement with the 3D-QSAR model from CoMFA. The combined CoMFA and docking study suggests the following substituent selections: substituent R(2) should be a kind of H-N-thienyl or CH(3)-N-thienyl group; substituent R(5) should be a kind of COO-tBu or COOEt group; and substituent R(4) should be a CH(2)CH(3) or 2-thienyl group. The docking analysis also shows that the binding sites fall just at the joint regions between AP-1 (or NF-kappaB) and DNA, where these compounds can effectively prevent free AP-1 and NF-kappaB from binding to DNA, and this may be the reason that derivatives with pyrimidine substituents have an inhibition function. In addition, a very interesting finding was that the binding sites of both AP-1 and NF-kappaB have a common structural characteristic, thereby providing a reasonable explanation for the dual inhibition functions of these compounds towards both AP-1 and NF-kappaB. These theoretical results help to deepen our understanding of the inhibition mechanism of these pyrimidine substituent derivatives, and will aid in directing further drug-molecular design.

Binding conformations and QSAR of CA-4 analogs as tubulin inhibitors.

A theoretical study on the binding conformations and the quantitative structure-activity relationship (QSAR) of combretastatin A4 (CA-4) analogs as inhibitors toward tubulin has been carried out using docking analysis and comparative molecular field analysis (CoMFA). The appropriate binding orientations and conformations of these compounds interacting with tubulin were revealed by the docking study; and a 3D-QSAR model showing significant statistical quality and satisfactory predictive ability was established, in which the correlation coefficient (R(2)) and cross-validation coefficient (q(2)) were 0.955 and 0.66, respectively. The same model was further applied to predict the pIC(50) values for 16 congeneric compounds as external test set, and the predictive correlation coefficient R(2)(pred) reached 0.883. Other tests on additional validations further confirmed the satisfactory predictive power of the model. In this work, it was very interesting to find that the 3D topology structure of the active site of tubulin from the docking analysis was in good agreement with the 3D-QSAR model from CoMFA for this series of compounds. Some key structural factors of the compounds responsible for cytotoxicity were reasonably presented. These theoretical results can offer useful references for understanding the action mechanism and directing the molecular design of this kind of inhibitor with improved activity.

[Luminescence dynamics analysis on ruthenium polypyridyl complexes bonding to DNA].

Time-resolved spectra of six kinds of ruthenium polypyridyl complexes [Ru(L)2 (R)]2+ (L = bpy, phen, bpy = 2,2'-bipyridine, phen = 1,10-phenanthroline, R = 7-CH3-dppz, 7-F-dppz, dpbpd(NH2)2) bonding to calf thymus DNA in aqueous solution were compared and analyzed by using the three energy level kinetic model. And the effects of the substituent groups on the interaction ways for the ruthenium complexes bonding to DNA were discussed. The result shows that first, the six complexes all show two binding modes on bonding to DNA, i.e. the side-on binding mode and the perpendicular binding mode, and the later one is considered as a main binding way. Second, the properties of substituent groups have an important impact on the relative weight of the two binding modes. The conclusion offers a dynamics argument to study the interaction mechanism for the complex bonding to DNA further.

Binding orientations, QSAR, and molecular design of thiophene derivative inhibitors.

A theoretical study on binding orientations and quantitative structure-activity relationship of thiophene derivatives as inhibitors towards tubulin has been carried out by using the docking analysis and the comparative molecular field analysis. The appropriate binding orientations and conformations of these compounds interacting with tubulin were revealed by docking study; and a 3D-quantitative structure-activity relationship model showing significant statistical quality and satisfying predictive ability was established, in which the correlation coefficient (R(2)) and cross-validation coefficient (q(2)) are 0.949 and 0.743, respectively. The same model was further applied to predict the pIC(50) values for nine congeneric compounds as external test set, and the predictive correlation coefficient R(pred)(2) reaches 0.929, thus the predictive ability of this 3D-quantitative structure-activity relationship model can be further confirmed. Some key structural factors of the compounds responsible for cytotoxicity were discussed in detail. Based on these structural factors, three new compounds with higher activity have been designed, and their cytotoxicities were also predicted by the established 3D-quantitative structure-activity relationship model from comparative molecular field analysis as well as the docking analysis. We hope these theoretical results can be confirmed by experimental work.

A theoretical study on the hydrolysis process of two Keppler-type antitumor complexes [TzH][trans-RuCl4(Tz)2] and [2-NH2TzH][trans-RuCl4(2-NH2Tz)2].

The hydrolysis processes of two Keppler-type antitumor ruthenium(III) complexes of [TzH][trans-RuCl4(Tz)2] (TzICR) and [2-NH2TzH][trans-RuCl4(2-NH2Tz)2] ((2-NH2)TzICR) have been investigated by using density functional theory (DFT) method, and the solvent effect was also considered and calculated by conductor-like polarizable calculation model (CPCM). The structural characteristics and the detailed energy profiles for the hydrolysis processes of title complexes have been obtained. The analysis of thermodynamic and kinetic characteristics of hydrolysis reaction suggests the following: For the 1st hydrolysis step, the complex TzICR has a lower hydrolysis rate than the reported drug [ImH][trans-RuCl4Im2](ICR, Im=imidazole). However, complex (2-NH2)TzICR has obviously a higher hydrolysis rate than TzICR and ICR. The result is in good agreement with the experimental one and the related regularity was further explained in theory. For the 2nd hydrolysis step, it is very significant to find that the formation of cis-diaqua products is thermodynamically preferred to that of trans isomers. Combining with the hydrolysis action mechanism of cisplatin, this is related to the so-called "cis effect", in which the cis-diaqua products are advantageous to binding to pertinent biomolecular targets. Therefore, the cis-diaqua products can be expected to be important precursors for the biological actions. These theoretical results would help to understand the action mechanism of these potential drugs with the pertinent biomolecular target.

CoMFA and docking studies of 2-phenylindole derivatives with anticancer activity.

Three-dimensional (3D) quantitative structure-activity relationship (QSAR) and docking studies of 43 tubulin inhibitors, 2-phenylindole derivatives with anticancer activity against human breast cancer cell line MDA-MB 231, have been carried out. The established 3D-QSAR model from the comparative molecular field analysis (CoMFA) in training set shows not only significant statistical quality, but also satisfying predictive ability, with high correlation coefficient value (R(2)=0.910) and cross-validation coefficient value (q(2)=0.705). Moreover, the predictive ability of the CoMFA model was further confirmed by a test set, giving the predictive correlation coefficient (R(2)(pred)) of 0.688. Based on the CoMFA contour maps and docking analyses, some key structural factors responsible for anticancer activity of this series of compounds were revealed as follows: the substituent R(1) should have higher electronegativity; the substituent R(2) should be linear alkyl with four or five carbon atoms in length; and the substituent R(3) should be selected to OCH(3)-kind group whereas should not be selected to CF(3)-kind group. Meanwhile, the interaction information between target and ligand was presented in detail. Such results can offer some useful theoretical references for understanding the action mechanism, designing more potent inhibitors and predicting their activities prior to synthesis.

Electronic structures, DNA-binding and spectral properties of Co(III) complexes [Co(bpy)2(L)]3+ (L=pip, odhip, hnoip).

Studies on the electronic structures and trend in DNA-binding affinities of a series of Co(III) complexes have been carried out, using the density functional theory (DFT) at the B3LYP/LanL2DZ level. The optimized geometric structures of these Co(III) complexes in aqueous solution are more close to experimental data than those in vacuo. The electronic structures of these Co(III) complexes were analyzed on the basis of their geometric structures optimized in aqueous solution, and the trend in the DNA-binding constants (K(b)) was reasonably explained. In addition, the electronic absorption spectra of these complexes were calculated and simulated in aqueous solution using the time dependent DFT (TDDFT) at the B3LYP/LanL2DZ level. The calculated absorption spectra of these Co(III) complexes in aqueous solution are in satisfying agreement with experimental results, and the properties of experimental absorption bands have been theoretically explained in detail. Meanwhile, in order to explore the solvent effect on the absorption spectra of these Co(III) complexes, their absorption spectra in vacuo were also calculated, and the results show that the calculated absorption spectra of Co(III) complexes are greatly influenced by the solvent effect.

Binding to DNA purine base and structure-activity relationship of a series of structurally related Ru(II) antitumor complexes: a theoretical study.

The thermodynamics of the binding of a series of structurally related Ru(II) antitumor complexes, that is, alpha-[Ru(azpy)2Cl2] 1, beta-[Ru(azpy)2Cl2] 2, alpha-[Ru(azpy)(bpy)Cl2] 3, and cis-[Ru(bpy)2Cl2] 4 to DNA purine bases (gunine, adenine at N7 site) has been studied by using the DFT method. The binding of imine form of 9-methyladenine (9-MeAde) to the Ru(II) moiety in a didentate fashion via its N6 and N7 atoms was also considered. The geometrical structures of the DNA model base adducts were obtained at the B3LYP/(LanL2DZ + 6-31G(d)) level in vacuo. The following exact single-point energy calculations were performed at the B3LYP/(LanL2DZ(f)+6-311+G(2d, 2p)) level both in vacuo and in aqueous solution using the COSMO model. The bond dissociation enthalpies and free energies, reaction enthalpies and free energies both in the gas phase and in aqueous solution for all considered Ru(II)-DNA model base adducts were obtained from the computations. The calculated bond dissociation enthalpies and free energies allow us to build a binding affinity order for the considered Ru(II)-DNA model base adducts. The theoretical results show that the guanine N7 is a preferred site for this series of complexes and support such an experimental fact that alpha-[Ru(azpy)(bpy)(9-EtGua)H2O](2+) (3-(9-EtGua)) is isomerized to alpha'-[Ru(azpy)(bpy)(9-EtGua)H2O](2+) (3'-(9-EtGua)). On the basis of structural and thermodynamical characteristics, the possible structure-activity relationship was obtained, and the distinct difference in cytotoxicities of this series of structurally related antitumor complexes was explained theoretically.

Tricationic pyridium porphyrins appending different peripheral substituents: experimental and DFT studies on their interactions with DNA.

Four tricationic pyridium porphyrins appending hydroxyphenyl, methoxyphenyl, propionoxyphenyl or carboxyphenyl group at meso-20-position of porphyrin core have been synthesized and their abilities to bind and cleave DNA have been investigated. Using a combination of absorption, fluorescence, circular dichroism (CD) spectra, thermal DNA denaturation as well as viscosity measurements, their binding modes and intrinsic binding constants (K(b)) to calf DNA (CT DNA) were comparatively studied and also compared with those of 5,10,15,20-tetrakis(1-methylpyridinium-4-yl)porphyrin (TMPyP). The results suggest that the K(b) values of these porphyrins are greatly influenced by the number of positive charges and steric hindrance. Theoretical calculations applying the density functional theory (DFT) have been carried out and explain their DNA-binding properties reasonably. The efficiency of DNA photocleavage by these porphyrins shows high dependence on the values of K(b).

Experimental and DFT studies on DNA binding and photocleavage of two cationic porphyrins. Effects of the introduction of a carboxyphenyl into pyridinium porphyrin.

The DNA-binding affinities and DNA photocleavage abilities of cationic porphyrin, 5-(4-carboxyphenyl)-10,15,20-tris(4-methylpyridiniumyl)porphyrin (CTMPyP), and its reference compound meso-tetrakis(N-methyl-4-pyridiniumyl)porphyrin (H2TMPyP) have been investigated. The DNA-binding behaviors of the two compounds in NaH2PO4 buffer were compared systematically by using absorption, fluorescence and circular dichroism (CD) spectra, thermal denaturation as well as viscosity measurements. The experimental results show that CTMPyP binds to DNA in an outside binding mode, while H2TMPyP in an intercalative mode. Photocleavage experiments reveal that both two compounds employ 1O2-mediated mechanism in cleaving DNA and H2TMPyP can cleave DNA more efficiently than CTMPyP. Theoretical calculations were carried out with the density functional theory (DFT), and the calculated results indicate that the character and energies of some frontier orbitals of CTMPyP are quite different from those of H2TMPyP. These theoretical results can be used to explain their different DNA-binding modes and affinities to a certain extent.

Two new sesquiterpenoids from the soft coral Sinularia polydactyla (Ehreberg).

Two new sesquiterpenoids, polydactins A (1) and B (2) and a known sesquiterpene, 10alpha-hydroxycadin-4-en-15-al (3), were isolated from the soft coral Sinularia polydactyla (Ehreberg). Their structures were determined mainly by spectroscopic methods. Polydactin A (1) showed moderate cytotoxic activities against human oral epidermoid carcinoma cell lines (KB) and human breast carcinoma (MCF) tumour cell lines (in vitro).

DNA binding and photocleavage properties of a novel cationic porphyrin-anthraquinone hybrid.

A novel cationic porphyrin-anthraquinone (Por-AQ) hybrid has been synthesized and characterized. Using the combination of absorption titration, fluorescence spectra, circular dichroism (CD) as well as viscosity measurements, the binding properties of the hybrid to calf thymus (CT) DNA have been investigated compared with its parent porphyrin. The experimental results show that at low [Por]/[DNA] ratios, the parent porphyrin binds to DNA in an intercalative mode while the hybrid binds in a combined mode of outside binding (for porphyrin moiety) and partial intercalation (for anthraquinone). Ethidium bromide (EB) competition experiment determined the binding affinity constants (K(app)) of the compounds for CT DNA. Theoretical calculational results applying the density functional theory (DFT) can explain the different DNA binding behaviors reasonably. (1)O(2) was suggested to be the reactive species responsible for the DNA photocleavage of porphyrin moieties in both two compounds. The wavelength-depending cleavage activities of the compounds were also investigated.

QSAR, action mechanism and molecular design of flavone and isoflavone derivatives with cytotoxicity against HeLa.

The quantitative structure-activity relationship (QSAR) of 32 flavone and isoflavone derivatives with cytotoxicity expressed as pGC50, which is defined as the negative value of the logarithm of necessary molar concentration of this series of compounds to cause 50% growth inhibition against the human cervical epithelioid carcinoma cell line (HeLa), has been studied by using the density functional theory (DFT), molecular mechanics (MM2) and statistical methods. In order to obtain QSAR model with high predictive ability, the original dataset was randomly divided into a training set comprising 26 compounds and a test set comprising the rest 6 compounds. An optimal model for the training set with significant statistical quality (RA2=0.852) and predictive ability (q2=0.818) was established. The same model was further applied to predict pGC50 values of the 6 compounds in the test set, and the resulting predictive correlation coefficient Rpred2 reaches 0.738, further showing that this QSAR model has high predictive ability. It is very interesting to find that the cytotoxicities of these compounds against HeLa appear to be mainly governed by two quantum-chemical factors, i.e., the energy (ELUMO) of the lowest unoccupied molecular orbital (LUMO) and the net charges of C atom at site 6 on aromatic rings (QC6). Here the possible action mechanism of these compounds was analyzed and discussed in detail, in particular, the fact why the flavone derivatives have considerably higher cytotoxicity than isoflavone derivatives was reasonably explained. Based on this QSAR equation, 5 new compounds with higher cytotoxicity have been theoretically designed. Such results can offer useful theoretical references for experimental works.