共查询到20条相似文献,搜索用时 46 毫秒
1.
B. K. Sharma Kirti Sarbhai P. Singh Susheela Sharma 《Journal of enzyme inhibition and medicinal chemistry》2013,28(3):437-443
The affinity profiles for the bovine adenosine receptors, A1 and A2A, of a series of 1,8-naphthyridine derivatives were quantitatively analyzed using physicochemical and structural parameters of the substituents, present at varying positions of the molecules. The derived significant correlation, for bovine A1 receptor, suggested that a R1 substituent having a higher van der Waals volume, a R2 substituent being a hydrogen-bond donor and a R3 substituent able to transmit a higher field effect are helpful in augmenting the pKi of a compound. Similarly the study, pertaining to bovine A2A receptor, revealed that a less bulky substituent at R2 and a strong electron-withdrawing substituent at R3 are desirable in improving the binding affinity of a compound while substituents at R1 remain insignificant to any interaction. 相似文献
2.
Chao Zhang Yongzhong Jia Yan Jing Huaiyou Wang Kai Hong 《Journal of molecular modeling》2014,20(8):1-8
Interactions between the NO2 group and 13 different substituents (BF2, BH2, CF3, CH3, CHO, CN, F, NH2, NMe2, NO2, NO, OH, OMe) were investigated computationally for bicyclo[2.2.2]octane (BCO) and benzene substituted at 1,4 and 1,3 positions in the ring. Three methods were employed to estimate the character and strength of the substituent effect: substituent effect stabilization energy (SESE), sigma/pi electron donor acceptor index (sEDA/pEDA) and substituent active region (cSAR) parameter. For the first time the sEDA/pEDA parameters were calculated not for the ring but for the NO2 group. All calculations were performed at the B3LYP/6-31G(d,p) level of theory. For 1,4 derivatives, a direct comparison of slopes of linear regressions between BCO and benzene reveals a much better transmission of the substituent effect in the latter. The ratio of slopes (benzene over BCO) is always larger than 4. It follows that the resonance effects, which are absent in the BCO, dominate in this case. For 1,3 derivatives, because of much lower correlation coefficients, estimated standard deviations (ESD) were used to calculate the ratio instead of the slopes. For these systems the ratio is much closer to the unity, which indicates that only the sigma/through space effects are present and they are of similar magnitude in benzene and BCO. It follows from natural population analysis (NPA) charges that the substituent effect in the studied systems is due mainly to through-space interactions. Figure
What is the nature of the substituent effect 相似文献
3.
Lack of experimental findings on the spectrum of cephalosporin allergenic determinants has hindered diagnosis of adverse reactions to these drugs and retarded understanding of allergenic cross-reactions between cephalosporins and between cephalosporins and penicillins. Subjects allergic to the widely used cephalosporin antibiotic cefaclor have serum immuno globulin (Ig) E antibodies that react with the drug. Quantitative hapten inhibition studies employing sera from subjects allergic to cefaclor revealed fine structual recognition differences between the combining site specificities of cefaclor-reactive IgE antibodies in the sera of different subjects. Unlike penicillins, where discrete side chain or thiazolidine ring determinants alone may be recognized, IgE binding determinants on cefaclor encompassed the entire molecule. Fine structural recognition specificity differences at positions R1 (side-chain) and R2 (substituent attached to dihydrothiazine ring) were detected between IgE antibodies in different sera. Some antibodies showed clear preferential recognition of the aminobenzyl group at position R1 and Cl at R2 while with others, a greater degree of recognition tolerance was seen at R1 where, for example, the aminohydroxybenzyl or aminodihydrobenzyl groups were recognized, and at R2 where a methyl or even an ester group was tolerated. As with the penicillins, cephalosporins as allergens cannot simply be considered as a group of compounds with a common allergenic determinant structure. IgE antibodies that bind to cefaclor show great heterogeneity indicated by clear, fine structural differences in recognition of the R1 and R2 groups on the drug. 相似文献
4.
Three-dimensional quantitative structure–activity relationship studies were performed on a series of 88 histamine receptor
4 (H4R) antagonists in an attempt to elucidate the 3D structural features required for activity. Several in silico modeling
approaches, including comparative molecular field analysis (CoMFA), comparative similarity indices analysis (CoMSIA), molecular
docking, and molecular dynamics (MD), were carried out. The results show that both the ligand-based CoMFA model (Q
2 = 0.548, R
ncv2 = 0.870, R
pre2 = 0.879, SEE = 0.410, SEP = 0.386) and the CoMSIA model (Q
2 = 0.526, R
ncv2 =0.866, R
pre2 = 0.848, SEE = 0.416, SEP = 0.413) are acceptable, as they show good predictive capabilities. Furthermore, a combined analysis
incorporating CoMFA, CoMSIA contour maps and MD results shows that (1) compounds with bulky or hydrophobic substituents at
positions 4–6 in ring A (R2 substituent), positively charged or hydrogen-bonding (HB) donor groups in the R1 substituent,
and hydrophilic or HB acceptor groups in ring C show enhanced biological activities, and (2) the key amino acids in the binding
pocket are TRP67, LEU71, ASP94, TYR95, PHE263 and GLN266. To our best knowledge, this work is the first to report the 3D-QSAR
modeling of these H4R antagonists. The conclusions of this work may lead to a better understanding of the mechanism of antagonism
and aid in the design of new, more potent H4R antagonists. 相似文献
5.
Theoretical design of energetic nitrogen-rich derivatives of 1,7-diamino-1,7-dinitrimino-2,4,6-trinitro-2,4,6-triazaheptane 总被引:2,自引:0,他引:2
The heats of formation (HOFs), energetic properties, and thermal stability of a series of 1,7-diamino-1,7-dinitrimino-2,4,6-trinitro-2,4,6-triazaheptane derivatives with different substituents, different numbers of substituents, and different original chains are found by using the DFT-B3LYP method. The results show that -NO2 or -NH2 is an effective substituent for increasing the gas-phase HOFs of the title compounds, especially -NO2 group. As the numbers of substitutents increase, their HOFs enhance obviously. Increasing the length of original chain is helpful for improving their HOFs. The substitution of -NO2 is useful for enhancing their detonation performances and the effects of the length of original chains on detonation properties are coupled with those of the substituents. An analysis of the BDE of the weakest bonds indicates that the substitution of the -NH2 groups and replacing the -NO2 groups of N-NO2 by the -NH2 groups are favorable for improving their thermal stability, while the substitution of -NO2 and increasing the length of original chain decrease their thermal stability. Considering the detonation performance and thermal stability, seven compounds may be considered as the potential candidates of high energy density compounds. 相似文献
6.
Anti-HCV activity of aryl diketoacid (ADK) has been characterized by its two pharmacophoric elements, α,β-diketo acid moiety and substituted aryl ring. In this study, as a part of our ongoing efforts to discover a novel anti-HCV compound mimicking the ADK scaffold, we designed 2-arylmethylaminomethyl-5,6-dihydroxychromone derivatives of which the dihydroxychromone moiety as well as the arylmethylaminomethyl substituent (R-PhCH2NHCH2-) were anticipated in exact match with the pharmacophore model of the ADK. The dihydroxychromone derivatives (3a-3u), thus prepared, showed biological activity in a substituent-dependent fashion, thereby leading to selective anti-HCV effect (EC50 = 2.0-14.0 μM, CC50 >100 μM) with the substituent groups such as Cl, Br, I, and Me specifically at the 3-position of the aromatic ring. 相似文献
7.
Electronic structure of 22 monosubstituted derivatives of benzene and exocyclically substituted fulvene with substituents:
B(OH)2, BH2, CCH, CF3, CH3, CHCH2, CHO, Cl, CMe3, CN, COCH3, CONH2, COOH, F, NH2, NMe2, NO, NO2, OCH3, OH, SiH3, SiMe3 were studied theoretically by means of Natural Bond Orbital analysis. It is shown, that sum of π-electron population of carbon
atoms of the fulvene and benzene rings, pEDA(F) and pEDA(B), respectively correlate well with Hammett substituent constants sp+ \sigma_{\rm{p}}^{+} and aromaticity index NICS. The substituent effect acting on pi-electron occupation at carbon atoms of the fulvene ring is
significantly stronger than in the case of benzene. Electron occupations of ring carbon atoms (except C1) in fulvene plotted
against each other give linear regressions with high correlation coefficients. The same is true for ortho- and para-carbon atoms in benzene. Positive slopes of the regressions indicate similar for fulvene and benzene kind of substituent effect
– mostly resonance in nature. Only the regressions of occupation at the carbon atom in meta- position of benzene against ortho- and para-positions gives negative slopes and low correlation coefficients. 相似文献
8.
Abstract The effect of pyrimidine base substitution on the sensitivity of oligonucleotides to nucleases has been studied with two series of self complementary deoxyoligonucleotides containing n-alkyl, n-(1-alkenyl) or n-(1-alkynyl) groups at C5 of pyrimidines, (dA-r5dU)10 and (dG-rsdC)6. The rate of hydrolysis by snake venom phosphodiesterase and in human serum decreased with increasing length and unsaturation of the substituent. 相似文献
9.
Presently, an in silico modeling was carried out on a series of 63 phosphonic acid-containing thiazole derivatives as fructose-1,6-bisphosphatase
(FBPase) inhibitors using CoMFA/CoMSIA and molecular docking methods. The CoMFA and CoMSIA models using 51 molecules in the
training set gave r
cv2 values of 0.675 and 0.619, r
2
values of 0.985 and 0.979, respectively. The systemic external validation indicated that our CoMFA and CoMSIA models possessed
high predictive powers with r
02 values of 0.995 and 0.994, r
m(test)2 values of 0.887 and 0.860, respectively. The 3D contour maps of the CoMFA and CoMSIA provided smooth and interpretable explanation
of the structure-activity relationship for the inhibitors. Molecular docking studies revealed that a phosphonic group was
essential for binding to the AMP binding site, and some key features were also identified. The analyses of the 3D contour
plots and molecular docking results permitted interesting conclusions about the effects of different substituent groups at
different positions of the common scaffold, which might guide the design of novel FBPase inhibitors with higher activity and
bioavailability. A set of 60 new analogues were designed by utilizing the results revealed in the present study, and were
predicted with significantly improved potencies in the developed models. The findings can be quite useful to aid the designing
of new fructose-1,6-biphophatase inhibitors with improved biological response. 相似文献
10.
S. Vittori E. Camaioni S. Costanzi R. Volpini K-N. Klotz G. Cristalli 《Nucleosides, nucleotides & nucleic acids》2013,32(4-5):739-740
Abstract In a search for potent and selective adenosine agonists it has been found that 2-hexynyladenosine-5′-N-ethyluronamide (HENECA) displays high affinity at rat A2A receptor combined with a good A2A vs A1 selectivity. The finding that HENECA shows good affinity also for A3 receptors prompted us to investigate the effect of various substituents in different positions of this molecule. 相似文献
11.
Human liver glycogen phosphorylase (hlGP), a key enzyme in glycogen metabolism, is a valid pharmaceutical target for the development of new anti-hyperglycaemic agents for type 2 diabetes. Inhibitor discovery studies have focused on the active site and in particular on glucopyranose based compounds with a β-1 substituent long enough to exploit interactions with a cavity adjacent to the active site, termed the β-pocket. Recently, C-β-d-glucopyranosyl imidazoles and 1, 2, 4-triazoles proved to be the best known glucose derived inhibitors of hlGP. Here we probe the β-pocket by studying the inhibitory effect of six different groups at the para position of 3-(β-d-glucopyranosyl phenyl)-5-phenyl-, 1, 2, 4-triazoles in hlGP by kinetics and X-ray crystallography. The most bioactive compound was the one with an amine substituent to show a Ki value of 0.43 μM. Structural studies have revealed the physicochemical diversity of the β-pocket providing information for future rational inhibitor design studies. 相似文献
12.
B. K. Sharma P. Singh Susheela Sharma 《Journal of enzyme inhibition and medicinal chemistry》2013,28(5):601-607
The antagonistic activities of derivatives of spiroethyl phenyl(substituted)piperazine at the 5-HT1A and adrenergic α1d receptors is quantitatively analyzed employing physicochemical and structural parameters. The derived correlation equation revealed that a substituent, other than 2-CH3 in the phenyl ring, having higher molar refraction, MR, and a substituent producing higher positive field effect at the 3-position are beneficial in increasing the binding affinity at the 5-HT1A receptor. In addition, a less hydrophobic substituent at the 4-position is also helpful in augmenting the binding affinity. The 5-R substituents which have higher MR values, however, elicit a detrimental effect. Two disubstituted compounds which are not present in the original data-set and have higher theoretical binding affinities are designed from the correlation equation. These compounds consisting of 2-OCH(CH3)2, 3-Cl and 2-C3H7, 3-Cl in the phenyl ring, have theoretical pKi values 10.57 and 10.12 respectively. For the adrenergic α1d receptor, a less bulky group at the 3-position with 5-Cl (or simply a 3-Cl) is advantageous in increasing the binding affinity. Likewise, a substituent exhibiting a less negative resonance effect at the 4-position and the substituent with low polarizability and showing more a negative resonance effect at the 5-position are suitable for enhancement of the binding affinity. The analysis provides the grounds for rationalizing substituent selection in designing better potency antagonists in the series. 相似文献
13.
We have synthesized 2- and 8-monosubstituted and 2,8-disubstituted derivatives of the cytokinin 6-(3-methyl-2-butenylamino)purine (N6-isopentenyladenine) and have shown the dependence of growth-promoting activity in the tobacco bioassay upon the position, number, and type of substituent. The representative substituent groups were MeS, Me, MeSO2, C6H5CH2S, HS and Cl. The 8-methyl derivative was exceptional in being more active than the unsubstituted parent compound. In general, substitution in the 8-position decreases activity less than substitution in the 2-position, with the exception of the electron-attracting methylsulfonyl. Substitution in both the 2- and 8-positions lowers the activity more than substitution at either single position on the adenine nucleus, with the exception of the 2,8-dimethyl derivative. The chloro and methylthio derivatives show activity in the same range as the methyl derivatives, and the mercapto compounds, which exist mainly as CS tautomers, show somewhat less activity than the corresponding methylthio compounds. Bulky (C6H5CH2S and MeSO2) and strongly electron-attracting (MeSO2) substituents cause relatively great reduction in cytokinin activity. 相似文献
14.
Thanh-Dao Tran Haeil Park Hyun Pyo Kim Gerhard F. Ecker Khac-Minh Thai 《Bioorganic & medicinal chemistry letters》2009,19(6):1650-1653
A series of 2′-hydroxychalcones has been synthesized and screened for their in vitro inhibitory activities of cyclooxygenase-2 catalyzed prostaglandin production from lipopolysaccharide-treated RAW 264.7 cells. Structure–activity relationship study suggested that inhibitory activity against prostaglandin E2 production was governed to a greater extent by the substituent on B ring of the chalcone, and most of the active compounds have at least two methoxy or benzyloxy groups on B ring. The relationship between chalcone structures and their PGE2 inhibitory activities was also interpreted by docking study on cyclooxygenase-2. 相似文献
15.
Interference of H-bonding and substituent effects in nitro- and hydroxy-substituted salicylaldehydes
Two intramolecular interactions, i.e., (1) hydrogen bond and (2) substituent effect, were analyzed and compared. For this
purpose, the geometry of 4- and 5-X-substituted salicylaldehyde derivatives (X = NO2, H or OH) was optimized by means of B3LYP/6-311 + G(d,p) and MP2/aug-cc-pVDZ methods. The results obtained allowed us to
show that substituents (NO2 or OH) in the para or meta position with respect to either OH or CHO in H-bonded systems interact more strongly than in the
case of di-substituted species: 4- and 3-nitrophenol or 4- and 3-hydroxybenzaldehyde by ∼31%. The substituent effect due to
the intramolecular charge transfer from the para-counter substituent (NO2) to the proton-donating group (OH) is ∼35% greater than for the interaction of para-OH with the proton-accepting group (CHO).
The total energy of H-bonding for salicylaldehyde, and its derivatives, is composed of two contributions: ∼80% from the energy
of H-bond formation and ∼20% from the energy associated with reorganization of the electron structure of the systems in question. 相似文献
16.
《Bioorganic & medicinal chemistry letters》2014,24(21):5055-5058
A series of 1-sulfonyl indolines was synthesized and evaluated for antiproliferative activity. The most potent compounds 9a and 9e showed significant cytotoxicity (IC50 in the range of 0.055–0.105 and 0.039–0.112 μM, respectively) against four human cancer cell lines HCT116, PC3, HepG2 and SK-OV-3. The structure–activity relationship of this series of sulfonamides, including the influence of azaheterocycle rings, substituent at the different positions of indoline, and the cyclopropane moiety, was described. 相似文献
17.
The electronic structure of tetrapyrrolidinodiborane [(C4H8N)2B]2 has been investigated by HeI and HeII UV photoelectron spectroscopy (UPS) and DFT/OVGF calculations. Our results indicate that the title molecule has very low first ionization energy and can be readily oxidized in solution. We estimated the magnitudes of alkyl substituent effects on nitrogen and boron atoms and the efficiency of boron atom to act as an electron density relay facilitating through-bond interactions between the nitrogen lone pairs. 相似文献
18.
C. Thibaudeau N. Nishizono Y. Sumita A. Matsuda J. Chattopadhyaya 《Nucleosides, nucleotides & nucleic acids》2013,32(4-5):1035-1053
Abstract The interplay of enthalpy of the gauche effect (ΔH°GE) of the [X3′-C3′-C4′-O4′] fragment in various 3′-substituted (X) 2′,3′-dideoxythymidine derivatives 1–7 and the inherent anomeric effect drives the two-state North ? South equilibrium in the constituent sugar moiety. The group electronegativity of 3′-OCF3 substituent in Marriott's, Inamoto's and Mullay's scales has been determined from simple calibration graphs correlating the group electronegativity of various 3′-substituents (X) in 2′,3′-dideoxythymidine derivatives 1–7 with the experimental strength (ΔH°GE) of the [X3′-C3′-C4′-O4′] gauche effect. ΔH°GE has been experimentally determined from pseudorotational analyses of temperature-dependent 3JHH coupling constants, and can be used as an unambiguous tool for direct experimental estimation of the group electronegativity of a specific substituent covalently attached to 3′-carbon of 2′,3′-dideoxythymidine, which can be compared, in turn, with the theoretical estimation carried out according to Marriott's or Inamoto's procedure. Inconsistency found between theoretical values in Marriott's and Inamoto's scales, on the one hand, and between our experimental estimate and the theoretical value in Marriott's scale, on the other, have been solved by refining the electronegativity scale using our experimental data for 1–7. 相似文献
19.
Zinc complexes of pyruvic and glyoxylic acid oximes have been investigated as potential precursors for single source chemical vapour deposition (SSCVD) of ZnO thin films. The X-ray crystal structures of the complexes and of their -NOMe analogues reveal markedly different coordination and intermolecular bonding patterns. These structural differences, in conjunction with ligand substituent changes impart different responses to thermogravimetric analysis (TGA), and sublimation. The glyoxylic acid methyloxime Zn(O2CCHN(OMe))2 · 2H2O has volatility and thermolysis properties suitable for SSCVD of ZnO. 相似文献
20.
《Journal of molecular biology》2023,435(10):168049
Mirogabalin is a novel gabapentinoid drug with a hydrophobic bicyclo substituent on the γ-aminobutyric acid moiety that targets the voltage-gated calcium channel subunit α2δ1. Here, to reveal the mirogabalin recognition mechanisms of α2δ1, we present structures of recombinant human α2δ1 with and without mirogabalin analyzed by cryo-electron microscopy. These structures show the binding of mirogabalin to the previously reported gabapentinoid binding site, which is the extracellular dCache_1 domain containing a conserved amino acid binding motif. A slight conformational change occurs around the residues positioned close to the hydrophobic group of mirogabalin. Mutagenesis binding assays identified that residues in the hydrophobic interaction region, in addition to several amino acid binding motif residues around the amino and carboxyl groups of mirogabalin, are critical for mirogabalin binding. The A215L mutation introduced to decrease the hydrophobic pocket volume predictably suppressed mirogabalin binding and promoted the binding of another ligand, L-Leu, with a smaller hydrophobic substituent than mirogabalin. Alterations of residues in the hydrophobic interaction region of α2δ1 to those of the α2δ2, α2δ3, and α2δ4 isoforms, of which α2δ3 and α2δ4 are gabapentin-insensitive, suppressed the binding of mirogabalin. These results support the importance of hydrophobic interactions in α2δ1 ligand recognition. 相似文献