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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
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Farhan Ahmad Pasha Muhammad Muddassar Anil Kumar Srivastava Seung Joo Cho 《Journal of molecular modeling》2010,16(2):263-277
Members of the epidermal growth factor receptor (EGFR) family of proteins are frequently overactive in solid tumors. A relatively
new therapeutic approach to inhibit the kinase activity is the use of ATP-competitive small molecules. In silico techniques
were employed to identify the key interactions between inhibitors and their protein receptors. A series of EGFR inhibitory
anilinoquinolines was studied within the framework of hologram quantitative structure activity relationship (HQSAR), density
functional theory (DFT)-based QSAR, and three-dimensional (3D) QSAR (CoMFA/CoMSIA). The HQSAR analysis implied that substitutions
at certain sites on the inhibitors play an important role in EGFR inhibition. DFT-based QSAR results suggested that steric
and electronic interactions contributed significantly to the activity. Ligand-based 3D-QSAR and receptor-guided 3D-QSAR analyses
such as CoMFA and CoMSIA techniques were carried out, and the results corroborated the previous two approaches. The 3D QSAR
models indicated that steric and hydrophobic interactions are dominant, and that substitution patterns are an important factor
in determining activity. Molecular docking was helpful in identifying a bioactive conformer as well as a plausible binding
mode. The docked geometry-based CoMFA model with steric and electrostatic fields effect gave q
2 = 0.66, r
2 = = 0.94 with r
2
predictive = 0.72. Similarly, CoMSIA with hydrophobic field gave q
2 = 0.59, r
2 = 0.85 with r
2
predictive = 0.63. Bulky groups around site 3 of ring “C”, and hydrophilic and bulky groups at position 6 of ring “A” are desirable,
with a hydrophobic and electron-donating group at site 7 of ring “A” being helpful. Accordingly, potential EGFR inhibitors
may be designed by modification of known inhibitors. 相似文献
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Chai HF Liang XX Li L Zhao CS Gong P Liang ZJ Zhu WL Jiang HL Luo C 《Journal of molecular modeling》2011,17(8):1831-1840
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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3D-QSAR studies on the derivatives of 1-(3,3-diphenylpropyl)-piperidinyl amide and urea as CCR5 receptor antagonists were
performed by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA) methods to
rationalize the structural requirements responsible for the inhibitory activity of these compounds. The global minimum energy
conformer of the template molecule, the most active and pharmacokinetically stable molecule of the series, was obtained by
systematic search and used to build structures of the molecules in the dataset. The best predictions for the CCR5-receptor
were obtained with the CoMFA standard model (q
2 = 0.787, r
2 = 0.962) and CoMSIA model combined steric, electrostatic and hydrophobic fields (q
2 = 0.809, r
2 = 0.951). The predictive ability of CoMFA and CoMSIA were determined using a test set of 12 compounds giving predictive correlation
coefficients of 0.855 and 0.83, respectively, indicating good predictive power. Further, the robustness of the model was verified
by bootstrapping analysis. The contour maps produced by the CoMFA and CoMSIA models were used to identify the structural features
relevant to the biological activity in this series. Based on the CoMFA and CoMSIA analysis, we have identified some key features
in the series that are responsible for CCR5 antagonistic activity which may be used to design more potent 1-(3,3-diphenylpropyl)-piperidinyl
derivatives and predict their activity prior to synthesis.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
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Han Chu Qing-xiu He Jun-wei Wang Ya-ting Deng Juan Wang Yong Hu 《Journal of biomolecular structure & dynamics》2020,38(15):4567-4578
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Ki Hwan Kim Irina Gaisina Franck Gallier Denise Holzle Sylvie Y. Blond Andrew Mesecar Alan P. Kozikowski 《Journal of molecular modeling》2009,15(12):1463-1479
Molecular modeling and docking studies along with three-dimensional quantitative structure relationships (3D-QSAR) studies
have been used to determine the correct binding mode of glycogen synthase kinase 3β (GSK-3β) inhibitors. The approaches of
comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) are used for the
3D-QSAR of 51 substituted benzofuran-3-yl-(indol-3-yl)maleimides as GSK-3β inhibitors. Two binding modes of the inhibitors
to the binding site of GSK-3β are investigated. The binding mode 1 yielded better 3D-QSAR correlations using both CoMFA and
CoMSIA methodologies. The three-component CoMFA model from the steric and electrostatic fields for the experimentally determined
pIC50 values has the following statistics: R2(cv) = 0.386 nd SE(cv) = 0.854 for the cross-validation, and R2 = 0.811 and SE = 0.474 for the fitted correlation. F (3,47) = 67.034, and probability of R2 = 0 (3,47) = 0.000. The binding mode suggested by the results of this study is consistent with the preliminary results of
X-ray crystal structures of inhibitor-bound GSK-3β. The 3D-QSAR models were used for the estimation of the inhibitory potency
of two additional compounds. 相似文献
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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
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Ren J Nichols C Bird L Chamberlain P Weaver K Short S Stuart DI Stammers DK 《Journal of molecular biology》2001,312(4):795-805