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1.
Density functional theory analysis was performed to elucidate the impact of one-electron reduction upon the initial step of adenosylcobalamin-dependent enzymatic catalysis. The transition state (TS) corresponding to the Co–C bond cleavage and subsequent hydrogen abstraction from the substrate was located. The intrinsic reaction coordinate calculations predicted that the reaction consisting of Co–C5′ bond cleavage in [CoIII(corrin)]–Rib (where Rib is ribosyl) and hydrogen-atom abstraction from the CH3–CH2–CHO substrate occurs in a concerted fashion. The computed activation energy barrier of the reaction (15.0 kcal/mol) was lowered by approximately 54.5% in comparison with the reaction involving the positively charged cofactor model (Im–[CoIII(corrin)]–Rib+, where Im is imidazole; energy barrier = 33.0 kcal/mol). The Im base was detached during the TS search in the reaction involving the one-electron-reduced analogue. Thus, to compare the energetics of the two reactions, the axial Im ligand detachment energy for the Im–[CoIII(corrin)]–Rib model was computed [7.6 kcal/mol (gas phase); 4.6 kcal/mol (water)]. Consequently, the effective activation energy barrier for the reaction mediated by the Im-off [CoIII(corrin)]–Rib was estimated to be 22.6 kcal/mol, which implied an overall 31.5% reduction in the energetic demands of the reaction. Considering that the lengthened Co–Naxial bond has been observed in X-ray crystal structure studies of B12-dependent mutases, the catalytic impact induced by one-electron reduction of the cofactor is expected to be higher in the presence of the enzymatic environment.  相似文献   

2.
We have studied the influence of hydrogenation on the relative stability of the low-lying isomers of the anionic B7 cluster, computationally. It is known that the pure-boron B7 cluster has a doubly (σ- and π-) aromatic C6v (3A1) quasi-planar wheel-type triplet global minimum (structure 1), a low-lying σ-aromatic and π-antiaromatic quasi-planar singlet C2v (1A1) isomer 2 (0.7 kcal mol−1 above the global minimum), and a planar doubly (σ- and π-) antiaromatic C2v (1A1) isomer 3 (7.8 kcal mol−1 above the global minimum). However, upon hydrogenation, an inversion in the stability of the species occurs. The planar B7H2 (C2v, 1A1) isomer 4, originated from the addition of two hydrogen atoms to the doubly antiaromatic B7 isomer 3, becomes the global minimum structure. The second most stable B7H2 isomer 5, originated from the quasi-planar triplet wheel isomer 1 of B7, was found to be 27 kcal mol−1 higher in energy. The inversion in stability occurs due to the loss of the doubly aromatic character in the wheel-type global minimum isomer (C6v, 3A1) of B7 upon H2−addition. In contrast, the planar isomer of B7 (C2v, 1A1) gains aromatic character upon addition of two hydrogen atoms, which makes it more stable. Figure The B7H2-global minimum structure and its σ-aromatic and π-antiaromatic MOs Dedicated to Professor Dr. Paul von Ragué Schleyer on the occasion of his 75th birthday.  相似文献   

3.
4.
 The electrochemistry of a water-soluble fragment from the CuA domain of Thermus thermophilus cytochrome ba 3 has been investigated. At 25  °C, CuA exhibits a reversible reduction at a pyridine-4-aldehydesemicarbazone-modified gold electrode (0.1 M Tris, pH 8) with E° = 0.24 V vs NHE. Thermodynamic parameters for the [Cu(Cys)2Cu]+/0 electrode reaction were determined by variable-temperature electrochemistry (ΔS°rc = –5.4(12) eu, ΔS° = –21.0(12) eu, ΔH° = –11.9(4) kcal/mol;ΔG° = –5.6 (11) kcal/mol). The relatively small reaction entropy is consistent with a low reorganization energy for [Cu(Cys)2Cu]+/0 electron transfer. An irreversible oxidation of [Cu(Cys)2Cu]+ at 1 V vs NHE confirms that the CuII:CuII state of CuA is significantly destabilized relative to the CuII state of analogous blue-copper proteins. Received: 3 June 1996 / Accepted: 26 August 1996  相似文献   

5.
Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named A1, A2A, A2B and A3 (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A2B AR is the least extensively characterised of the adenosine receptors family. Despite these limitations, growing understanding of the physiological meaning of this target indicates promising therapeutic perspectives for specific ligands. As A2B AR signalling seems to be associated with pre/postconditioning cardioprotective and anti-inflammatory mechanisms, selective agonists may represent a new therapeutic group for patients suffering from coronary artery disease. Herein we present an overview of the recent advancements in identifying potent and selective A2B AR agonists reported in scientific and patent literature. These compounds can be classified into adenosine-like and nonadenosine ligands. Nucleoside-based agonists are the result of modifying adenosine by substitution at the N 6-, C2-positions of the purine heterocycle and/or at the 5′-position of the ribose moiety or combinations of these substitutions. Compounds 1-deoxy-1-{6-[N′-(furan-2-carbonyl)-hydrazino]-9H-purin-9-yl}-N-ethyl-β-D-ribofuranuronamide (19, hA1 K i = 1050 nM, hA2A K i = 1550 nM, hA2B EC50 = 82 nM, hA3 K i > 5 μM) and its 2-chloro analogue 23 (hA1 K i = 3500 nM, hA2A K i = 4950 nM, hA2B EC50 = 210 nM, hA3 K i > 5 μM) were confirmed to be potent and selective full agonists in a cyclic adenosine monophosphate (cAMP) functional assay in Chinese hamster ovary (CHO) cells expressing hA2B AR. Nonribose ligands are represented by conveniently substituted dicarbonitrilepyridines, among which 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide (BAY-60–6583, hA1, hA2A, hA3 EC50 > 10 μM; hA2B EC50 = 3 nM) is currently under preclinical-phase investigation for treating coronary artery disorders and atherosclerosis.  相似文献   

6.
Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named A1, A2A, A2B and A3 (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A2B AR is the least extensively characterised of the adenosine receptors family. Despite these limitations, growing understanding of the physiological meaning of this target indicates promising therapeutic perspectives for specific ligands. As A2B AR signalling seems to be associated with pre/postconditioning cardioprotective and anti-inflammatory mechanisms, selective agonists may represent a new therapeutic group for patients suffering from coronary artery disease. Herein we present an overview of the recent advancements in identifying potent and selective A2B AR agonists reported in scientific and patent literature. These compounds can be classified into adenosine-like and nonadenosine ligands. Nucleoside-based agonists are the result of modifying adenosine by substitution at the N 6-, C2-positions of the purine heterocycle and/or at the 5′-position of the ribose moiety or combinations of these substitutions. Compounds 1-deoxy-1-{6-[N′-(furan-2-carbonyl)-hydrazino]-9H-purin-9-yl}-N-ethyl-β-D-ribofuranuronamide (19, hA1 K i = 1050 nM, hA2A K i = 1550 nM, hA2B EC50 = 82 nM, hA3 K i > 5 μM) and its 2-chloro analogue 23 (hA1 K i = 3500 nM, hA2A K i = 4950 nM, hA2B EC50 = 210 nM, hA3 K i > 5 μM) were confirmed to be potent and selective full agonists in a cyclic adenosine monophosphate (cAMP) functional assay in Chinese hamster ovary (CHO) cells expressing hA2B AR. Nonribose ligands are represented by conveniently substituted dicarbonitrilepyridines, among which 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide (BAY-60–6583, hA1, hA2A, hA3 EC50 > 10 μM; hA2B EC50 = 3 nM) is currently under preclinical-phase investigation for treating coronary artery disorders and atherosclerosis. This article has previously been published in issue 4/4, under doi:.  相似文献   

7.
The complex of pesticidal metabolites produced byStreptomyces griseus LKS-1 consists of a peptide antibiotic (A), nonactic acids (B), macrotetrolides (C), pyrrolizines (D), and of cycloheximide. The latter unwanted phytotoxic compound was eliminated by treatment with mutagens. Combined approaches, including both genetic and physiological manipulations, resulted in the following alterations in the biosynthetic capacity: (1) A more than 80-fold increase in the production of C under a substantial decrease in the yields ofA, B andD, the ratio of the components ofC being steered toward the required more active ones; (2) a more than 300-fold increase in the production ofB under suppression of the formation ofA andC: (3) a 10-fold increase in the yields ofD under suppression ofA andC; (4 a significant increase in the yields ofA with eliminatingB, C andD. The level of inorganic phosphate in fermentation media and the sensitivity of the organism to carbon catabolite repression were important factors participating in the regulation of the above biosynthetic processes.  相似文献   

8.
A DFT study with QST3 approach method is used to calculate kinetic, thermodynamic, spectral and structural data of tautomers and transition state structures of some N-hydroxy amidines. All tautomers and transition states are optimized at the B3LYP/6-311++g** and B3LYP/aug-cc-pvtz level, with good agreement in energetic result with energies obtained from CBS-QB3, a complete basis set composite energy method. The result shows that the tautomer a (amide oxime) is more stable than the tautomer b (imino hydroxylamine) as is reported in the literature. In addition, our finding shows that, the energy difference between two tautomers is only in about 4–10 kcal/mol but the barrier energy found in traversing each tautomer to another one is in the range of 33–71 kcal/mol. Therefore, it is impossible to convert these two tautomers to each other at room temperature. Additionally, transition state theory is applied to estimate the barrier energy and reaction rate constants of the hydrogen exchange between tautomers in presence of 1–3 molecules of water. The computed activation barrier shows us that the barrier energy of solvent assisted tautomerism is about 9–20 kcal/mol and lower than simple tautomerism and this water-assisted tautomerism is much faster than simple tautomerism, especially with the assisting two molecules of water.  相似文献   

9.
High level ab initio and density functional calculations, extrapolated to QCISD(T)/6-311+G(3df,2p)//MP2/6-31+G**+ZPE, reveal that cyclic ion pairs can form in the hydrogen bonded complexes of haloboric acids BHnX3-n–HX, X=F, Cl, with Lewis bases HX, H2O, CH3OH, and NH3, even in isolation (e.g., in the gas phase). The intrinsic acidities (deprotonation energies) required for protonation of these bases with formation of gas phase ion pairs are calculated to be <295 kcal/mol for water, <301 kcal/mol for methanol, and <306 kcal/mol for ammonia; such values are common for acidic sites in zeolites. All gas phase ion pairs prefer symmetric bidentate or tridentate structures. In the other cases where hydrogen bonded complexes prevail, symmetric ion pair-like transition structures for multiple hydrogen exchange are computed.Supplementary material to this paper is available in electronic form at http://dx.doi.org/10.1007/s0089400060563  相似文献   

10.
GP catalyzes the phosphorylation of glycogen to Glc-1-P. Because of its fundamental role in the metabolism of glycogen, GP has been the target for a systematic structure-assisted design of inhibitory compounds, which could be of value in the therapeutic treatment of type 2 diabetes mellitus. The most potent catalytic-site inhibitor of GP identified to date is spirohydantoin of glucopyranose (hydan). In this work, we employ MD free energy simulations to calculate the relative binding affinities for GP of hydan and two spirohydantoin analogues, methyl-hydan and n-hydan, in which a hydrogen atom is replaced by a methyl- or amino group, respectively. The results are compared with the experimental relative affinities of these ligands, estimated by kinetic measurements of the ligand inhibition constants. The calculated binding affinity for methyl-hydan (relative to hydan) is 3.75 +/- 1.4 kcal/mol, in excellent agreement with the experimental value (3.6 +/- 0.2 kcal/mol). For n-hydan, the calculated value is 1.0 +/- 1.1 kcal/mol, somewhat smaller than the experimental result (2.3 +/- 0.1 kcal/mol). A free energy decomposition analysis shows that hydan makes optimum interactions with protein residues and specific water molecules in the catalytic site. In the other two ligands, structural perturbations of the active site by the additional methyl- or amino group reduce the corresponding binding affinities. The computed binding free energies are sensitive to the preference of a specific water molecule for two well-defined positions in the catalytic site. The behavior of this water is analyzed in detail, and the free energy profile for the translocation of the water between the two positions is evaluated. The results provide insights into the role of water molecules in modulating ligand binding affinities. A comparison of the interactions between a set of ligands and their surrounding groups in X-ray structures is often used in the interpretation of binding free energy differences and in guiding the design of new ligands. For the systems in this work, such an approach fails to estimate the order of relative binding strengths, in contrast to the rigorous free energy treatment.  相似文献   

11.
The seemingly simple proton abstraction reactions underpin many chemical transformations, including isomerization reactions, and are thus of immense biological significance. Despite the energetic cost, enzyme-catalyzed proton abstraction reactions show remarkable rate enhancements. The pathways leading to these accelerated rates are numerous and on occasion partly enigmatic. The isomerization of the steroid Δ5-androstene-3,17-dione by the glutathione transferase A3-3 in mammals was investigated to gain insight into the mechanism. Particular emphasis was placed on the nature of the transition state, the intermediate suspected of aiding this process, and the hydrogen bonds postulated to be the stabilizing forces of these transient species. The UV-visible detection of the intermediate places this species in the catalytic pathway, whereas fluorescence spectroscopy is used to obtain the binding constant of the analog intermediate, equilenin. Solvent isotope exchange reveals that proton abstraction from the substrate to form the intermediate is rate-limiting. Analysis of the data in terms of the Marcus formalism indicates that the human glutathione transferase A3-3 lowers the intrinsic kinetic barrier by 3 kcal/mol. The results lead to the conclusion that this reaction proceeds through an enforced concerted mechanism in which the barrier to product formation is kinetically insignificant.  相似文献   

12.
Abstract

A single-point substitution of the O4′ oxygen by a CH2 group at the sugar residue of A 6 (i.e. 2′-deoxyaristeromycin moiety) in a self-complementary DNA duplex, 5′- d(C1G2C3G4A5A6T7T8C9G10C11G12)2 ?3, has been shown to steer the fully Watson-Crick basepaired DNA duplex (1A), akin to the native counterpart, to a doubly A 6:T7 Hoogsteen basepaired (1B) B-type DNA duplex, resulting in a dynamic equilibrium of (1A)→←(1B): Keq = k1/k-1 = 0.56±0.08. The dynamic conversion of the fully Watson-Crick basepaired (1A) to the partly Hoogsteen basepaired (1B) structure is marginally kinetically and thermodynamically disfavoured [k1 (298K) = 3.9± 0.8 sec?1; δH°? = 164±14 kJ/mol;-TδS°? (298K) = ?92 kJ/mol giving a δG298°? of 72 kJ/mol. Ea (k1) = 167±14 kJ/mol] compared to the reverse conversion of the Hoogsteen (1B) to the Watson-Crick (1A) structure [k-1 (298K) = 7.0±0.6 sec-1, δH°? = 153±13 kJ/mol;-TδS°? (298K) = ?82 kJ/mol giving a δG298°? of 71 kJ/mol. Ea (k-1) = 155±13 kJ/mol]. A comparison of δG298°? of the forward (k1) and backward (k-1) conversions, (1A)→←(1B), shows that there is ca 1 kJ/mol preference for the Watson-Crick (1A) over the double Hoogsteen basepaired (1B) DNA duplex, thus giving an equilibrium ratio of almost 2:1 in favour of the fully Watson-Crick basepaired duplex. The chemical environments of the two interconverting DNA duplexes are very different as evident from their widely separated sets of chemical shifts connected by temperature-dependent exchange peaks in the NOESY and ROESY spectra. The fully Watson-Crick basepaired structure (1A) is based on a total of 127 intra, 97 inter and 17 cross-strand distance constraints per strand, whereas the double A 6:T7 Hoogsteen basepaired (1B) structure is based on 114 intra, 92 inter and 15 cross-strand distance constraints, giving an average of 22 and 20 NOE distance constraints per residue and strand, respectively. In addition, 55 NMR-derived backbone dihedral constraints per strand were used for both structures. The main effect of the Hoogsteen basepairs in (1B) on the overall structure is a narrowing of the minor groove and a corresponding widening of the major groove. The Hoogsteen basepairing at the central A 6:T7 basepairs in (1B) has enforced a syn conformation on the glycosyl torsion of the 2′- deoxyaristeromycin moiety, A 6, as a result of substitution of the endocyclic 4′-oxygen in the natural sugar with a methylene group in A 6. A comparison of the Watson-Crick basepaired duplex (1A) to the Hoogsteen basepaired duplex (1B) shows that only a few changes, mainly in α, σ and γ torsions, in the sugar-phosphate backbone seem to be necessary to accommodate the Hoogsteen basepair.  相似文献   

13.
The importance and requirements for catalytic activation of sialyl donors are discussed, leading to the acid sensitive phosphite and phosphate moiety, respectively, as leaving group and nitriles as solvent. Therefore, from readily availableN-acetylneuraminic acid, derivative1 with phosphochloridites2a-f and Huenigs' base sialyl phosphites3a-f were prepared and isolated in high yields. Oxidation of3a, c withtert-butyl-hydroperoxide afforded the corresponding phosphates4a, c. As expected, phosphites3 could be activated in acetonitrile by catalytic amounts of TMSOTf; thus, from3a-e as donors and lactose derivatives8A, B as acceptors the ganglioside building blocks9A and9B, respectively, were obtained in good yields. The best results were obtained with diethyl phosphite derivative3a as sialyl donor, which exceeded by far the reults obtained with the corresponding phosphate derivative4a. Trisaccharide9B was transformed into known9A and into the fullyO-acetylated GM3-trisaccharide10.  相似文献   

14.
Abstract

Self-complementary decadeoxynucleotides, CCGATATCGG, CCAGATCTGG, CCCTG- CAGGG, GGGGGCCCCC, were designed and synthesized to estimate the A-philic free energy of CC/GG contacts.

First, regions of temperature-stability of the double-stranded conformation were determined for each 10-mer. Then, circular dichroism spectra were recorded for the B-family forms at different temperatures, counter-ion concentrations and trifluoroethanol contents.

A cooperative change typical of the B-A transition is observed in the CD spectra at a trifluoroethanol content specific for each duplex. The positions of half-transition points were functions not only of the nucleotide sequence but of the duplex length as well: the B to A transitions were hindered in these 10-mers in comparison with a lengthy DNA. The B-phility value was estimated to be 3 kcal/mol of 10-mer.

The B-A transition point was shown to drop with an increase in the number of CC/GG contacts in a duplex. The designed 10-mers made it possible to estimate quantitatively the A- phility of CC/GG contact as compared with an average DNA: (FA-FB)CC=0.2 Kcal/mol, (FA-FB)DNA=0.7 Kcal/mol.  相似文献   

15.
The electronic ground state of the peroxidase compound I π-cation radical has been changed from 2A2u to 2A1u by substituting deuterohemin for the protohemin of the native enzyme. Although the 2A1u ground state is the same one as that taken by the catalase compound I π-cation radical deuterohemin horseradish peroxidase possesses no catalase activity. It thus appears that the protein and not only the ground state of the compound I π-cation radical determines the reactivities of compounds I of horseradish peroxidase toward hydrogen donors.  相似文献   

16.
ETA subtype selective antagonists constitute a novel and potentially important class of agents for the treatment of pulmonary hypertension, heart failure, and other pathological conditions. In this paper, 60 benzodiazepine derivatives displaying potent activities against ETA and ETB subtypes of endothelin receptor were selected to establish the 3D-QSAR models using CoMFA and CoMSIA approaches. These models show excellent internal predictability and consistency, external validation using test-set 19 compounds yields a good predictive power for antagonistic potency. Statistical parameters of models were obtained with CoMFA-ETA (q 2 = 0.787, r 2 = 0.935, r 2 pred  = 0.901), CoMFA-ETB (q 2 = 0.842, r 2 = 0.984, r 2 pred  = 0.941), CoMSIA-ETA (q 2 = 0.762, r 2 = 0.971, r 2 pred  = 0.958) and CoMSIA-ETB (q 2 = 0.771, r 2 = 0.974, r 2 pred  = 0.953) respectively. Field contour maps (CoMFA and CoMSIA) corresponding to the ETA and ETB subtypes reflects the characteristic similarities and differences between these types. The results of this paper provide valuable information to facilitate structural modifications of the title compounds to increase the inhibitory potency and subtype selectivity of endothelin receptor.  相似文献   

17.
Summary.  The mechanism of the reaction of high temperature solid state catalytic isotope exchange (HSCIE) of hydrogen in peptides with spillover-tritium at 140–180°C was analyzed. This reaction was used for preparing [3H]enkephalins such as [3H]DALG with specific activity of 138 Ci/mmol and [3H]LENK with specific activity of 120 Ci/mmol at 180°C. The analogues of [3H]ACTG4–10 with specific activity of 80 Ci/mmol, [3H]zervamicin IIB with specific activity of 70 Ci/mmol and [3H]conotoxin G1 with specific activity 35 Ci/mmol were produced. The obtained preparations completely retained their biological activity. [3H]Peptide analysis using 3H NMR spectroscopy on a Varian UNITY-600 spectrometer at 640 MHz was carried out. The reaction ability of amino fragments in HSCIE was shown to depend both of their structures and on the availability and the mobility of the peptide chain. The reaction of HSCIE with the β-galactosidase from Termoanaerobacter ethanolicus was studied. The selected HSCIE conditions allow to prepare [3H] β-galactosidase with specific activity of 1440 Ci/mmol and completely retained its the enzymatic activity. Received November 30, 2001 Accepted January 31, 2002 Published online December 18, 2002 Acknowledgments The work was supported by the Russian Foundation for Basic Research, grant 01-04-48519a. Authors' address: Dr. Yurii A. Zolotarev, Institute of Molecular Genetics, Russian Academy of Sciences, pl. Kurchatova 2, 123182, Moscow, Russia, Fax: +7 (095) 196-0221, E-mail: zolya@img.ras.ru Abbreviations:HSCIE, the reaction of high temperature solid state catalytic isotope exchange; HS, hydrogen spillover; 3H NMR, tritium nuclear magnetic spectroscopy; CtxG1, conotoxin G1; AchR, acetylcholine receptor; HF, Hartree-Fock ab initio quantum-chemical calculation method  相似文献   

18.
Nα-vanillyl-Nω-nitroarginine (N ? 1) that combines the active functions of natural antioxidant and nitric oxide synthase inhibitor was developed for its neuroprotective properties. N ? 1 exhibited protective effects against hydrogen peroxide-induced cell damage and the inhibitory effect on nitric oxide ‘NO’ production induced by calcium ionophore in NG 108-15 cells. N ? 1 inhibited the constitutive NOS isolated from rat cerebellar in a greater extent than constitutive NOS from human endothelial cells. Low binding energy ( ? 10.2 kcal/mol) obtained from docking N ? 1 to nNOS supported the additional mode of action of N ? 1 as an nNOS inhibitor. The in vivo neuroprotective effect on kainic acid-induced nitric oxide production and neuronal cell death in rat brain was investigated via microdialysis. Rats were injected intra-peritonially with N ? 1 at 75 μmol/kg before kainic acid injection (10 mg/kg). The significant suppression effect on kainic acid-induced NO and significant increase in surviving cells were observed in the hippocampus at 40 min after the induction.  相似文献   

19.
Photo-induced C1′ hydrogen abstraction of 5-fluoro-2′-deoxyuridine was adopted as the key reaction for releasing 5-fluorouracil (5-FU) anticancer drug from oligonucleotide strands. After photoirradiation following 5-FU release, anticancer activity was expected. We demonstrated that oligonucleotide tetramer, d(AFUIUA), can release 5-FU under physiological conditions in a photo-responsive manner thorough photo-induced C1′ hydrogen abstraction, and that the 5-FU released from d(AFUIUA) having a phosphorothioate backbone clearly suppresses the proliferation of HeLa cells in a photo-responsive manner.  相似文献   

20.
Infection with hepatitis B virus (HBV) is a major cause of liver diseases such as cirrhosis and hepatocellular carcinoma. In our previous studies, we identified indole derivatives that have anti-HBV activities. In this study, we optimize a series of 5-hydroxy-1H-indole-3-carboxylates, which exhibited potent anti-HBV activities, using three-dimensional quantitative structure-activity relationship (3D QSAR) studies with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The lowest energy conformation of compound 3, which exhibited the most potent anti-HBV activity, obtained from systematic search was used as the template for alignment. The best predictions were obtained with the CoMFA standard model (q 2 = 0.689, r 2 = 0.965, SEE = 0.082, F = 148.751) and with CoMSIA combined steric, electrostatic, hydrophobic and H-bond acceptor fields (q 2 = 0.578, r 2 = 0.973, SEE = 0.078, F = 100.342). Both models were validated by an external test set of six compounds giving satisfactory prediction. Based on the clues derived from CoMFA and CoMSIA models and their contour maps, another three compounds were designed and synthesized. Pharmacological assay demonstrated that the newly synthesized compounds possessed more potent anti-HBV activities than before (IC50: compound 35a is 3.1 μmol/l, compound 3 is 4.1 μmol/l). Combining the clues derived from the 3D QSAR studies and from further validation of the 3D QSAR models, the activities of the newly synthesized indole derivatives were well accounted for. Furthermore, this showed that the CoMFA and CoMSIA models proved to have good predictive ability.  相似文献   

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