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1.
Ketthip Suphavanich Phornphimon Maitarad Supa Hannongbua Pichit Sudta Sunit Suksamrarn Yuthana Tantirungrotechai Jumras Limtrakul 《Monatshefte für Chemie / Chemical Monthly》2009,140(3):273-280
Abstract A new series of xanthone derivatives against the oral human epidermoid carcinoma (KB) cancer cell line is examined to determine
the relationship between the structural properties and the biological activity of these compounds—the 3-D quantitative structure–activity
relationship (3D-QSAR)—using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis
(CoMSIA). The best CoMFA and CoMSIA models were obtained using the atom-based alignment of 33 compounds, 22 training compounds
and 11 tested compounds, and these give desirable statistics; those for the CoMFA standard model were: r
cv2 = 0.691, r
2 = 0.998, S
press = 0.178, s = 0.014 and F = 1080.765, while CoMSIA combined steric, electrostatic, hydrophobic and hydrogen-bond acceptor fields: r
cv2 = 0.600, r
2 = 0.988, S
press = 0.206, s = 0.034 and F = 284.433. The 3D-QSAR models calculated satisfactory test set activities. The 3D-QSAR contour plots correlated strongly
with the experimental data for the binding topology. For this reason, these results would be beneficial for predicting affinities
with the compounds of interest, and they are advantageous for guiding the design and synthesis of new and more effective anticancer
agents.
Graphical abstract
A new and more effective anticancer agent of xanthone derivatives against the oral human epidermoid carcinoma (KB) cell line,
as investigated by CoMFA and CoMSIA analysis 相似文献
2.
Patchreenart Saparpakorn Ratsupa Thammaporn Supa Hannongbua 《Monatshefte für Chemie / Chemical Monthly》2009,15(7):587-594
Abstract
Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) based on the docked conformation were performed for 24 pyrazinone derivatives. All compounds were docked into the wild-type HIV-1 RT binding pocket and the lowest-energy docked configurations were used to construct the 3D QSAR models. The CoMFA and CoMSIA models enable good prediction of inhibition by the pyrazinones, with r\textcv2 r_{\text{cv}}^{2} = 0.703 and 0.735. Results obtained from CoMFA and CoMSIA based on the docking conformation of the pyrazinones are, therefore, powerful means of elucidating the mode of binding of pyrazinones and suggesting the design of new potent NNRTIs. 相似文献3.
Teixeira C Gomes JR Couesnon T Gomes P 《Journal of computer-aided molecular design》2011,25(8):763-775
Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) based on three-dimensional
quantitative structure–activity relationship (3D-QSAR) studies were conducted on a series (39 molecules) of peptidyl vinyl
sulfone derivatives as potential Plasmodium Falciparum cysteine proteases inhibitors. Two different methods of alignment were employed: (i) a receptor-docked alignment derived
from the structure-based docking algorithm GOLD and (ii) a ligand-based alignment using the structure of one of the ligands
derived from a crystal structure from the PDB databank. The best predictions were obtained for the receptor-docked alignment
with a CoMFA standard model (q
2 = 0.696 and r
2 = 0.980) and with CoMSIA combined electrostatic, and hydrophobic fields (q
2 = 0.711 and r
2 = 0.992). Both models were validated by a test set of nine compounds and gave satisfactory predictive r
2
pred values of 0.76 and 0.74, respectively. CoMFA and CoMSIA contour maps were used to identify critical regions where any change
in the steric, electrostatic, and hydrophobic fields may affect the inhibitory activity, and to highlight the key structural
features required for biological activity. Moreover, the results obtained from 3D-QSAR analyses were superimposed on the Plasmodium Falciparum cysteine proteases active site and the main interactions were studied. The present work provides extremely useful guidelines
for future structural modifications of this class of compounds towards the development of superior antimalarials. 相似文献
4.
Poonsiri Thipnate Montakarn Chittchang Nopporn Thasana Patchreenart Saparpakorn Poonsakdi Ploypradith Supa Hannongbua 《Monatshefte für Chemie / Chemical Monthly》2011,13(4):97-109
Abstract
The common structural requirements for cytotoxicity of lamellarins against two human breast cancer cell lines were determined using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. Twenty lamellarins were selected to serve as the training set, whereas another group of six compounds were used as the test set. The best CoMFA and CoMSIA models for both cell lines yielded satisfactory predictive ability with r cv2 values in the range of 0.659–0.728. Additionally, the contour maps obtained from both the CoMFA and CoMSIA models agreed well with the experimental results and may be used in the design of more potent cytotoxic compounds for human breast cancers. Both analyses not only suggested structural requirements of various substituents around the lamellarin skeleton for their cytotoxic activity against both human breast cancer cell lines but also revealed the molecular basis for the differences between the saturated and unsaturated D-rings of the lamellarins. 相似文献5.
Phosphoinositide-dependent protein kinase-1 (PDK1) is a Ser/Thr kinase which phosphorylates and activates members of the AGC
kinase group known to control processes such as tumor cell growth, protection from apoptosis, and tumor angiogenesis. In this
paper, CoMFA and CoMSIA studies were carried out on a training set of 56 conformationally rigid indolinone inhibitors of PDK1.
Predictive 3D QSAR models, established using atom fit alignment rule based on crystallographic-bound conformation, had cross-validated
(r
cv2) values of 0.738 and 0.816 and non-cross-validated (r
ncv2) values of 0.912 and 0.949 for CoMFA and CoMSIA models, respectively. The predictive ability of the CoMFA and CoMSIA models
was determined using a test set of 14 compounds, which gave predictive correlation coefficients (r
pred2) of 0.865 and 0.837, respectively. Structure-based interpretation of the CoMFA and CoMSIA field properties provided further
insights for the rational design of new PDK1 inhibitors.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
6.
Aihua Xie Srinivas Odde Sivaprakasam Prasanna Robert J. Doerksen 《Journal of computer-aided molecular design》2009,23(7):431-448
One of the most promising anticancer and recent antimalarial targets is the heterodimeric zinc-containing protein farnesyltransferase
(FT). In this work, we studied a highly diverse series of 192 Abbott-initiated imidazole-containing compounds and their FT
inhibitory activities using 3D-QSAR and docking, in order to gain understanding of the interaction of these inhibitors with
FT to aid development of a rational strategy for further lead optimization. We report several highly significant and predictive
CoMFA and CoMSIA models. The best model, composed of CoMFA steric and electrostatic fields combined with CoMSIA hydrophobic
and H-bond acceptor fields, had r
2 = 0.878, q
2 = 0.630, and r
pred2 = 0.614. Docking studies on the statistical outliers revealed that some of them had a different binding mode in the FT active
site based on steric bulk and available active site space, explaining why the predicted activities differed from the experimental
activities.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
7.
Fangfang Wang Wei Yang Ran Li Zhihai Sui Guijuan Cheng Bo Zhou 《Arabian Journal of Chemistry》2021,14(6):103144
Focal adhesion kinase (FAK) is a promising target for developing more effective anticancer drugs. To better understand the structure-activity relationships and mechanism of actions of FAK inhibitors, a molecular modeling study using 3D-QSAR, molecular docking, molecular dynamics simulations, and binding free energy analysis were conducted. Two types of satisfactory 3D-QSAR models were generated, comprising the CoMFA model (R2cv = 0.528, R2pred = 0.7557) and CoMSIA model (R2cv = 0.757, R2pred = 0.8362), for predicting the inhibitory activities of novel inhibitors. The derived contour maps indicate structural characteristics for substituents on the template. Molecular docking, molecular dynamic simulations and binding free energy calculations further reveal that the binding of inhibitors to FAK is mainly contributed from hydrophobic, electrostatic and hydrogen bonding interactions. In addition, some key residues (Arg14, Glu88, Cys90, Arg138, Asn139, Leu141, and Leu155) responsible for ligand-receptor binding are highlighted. All structural information obtained from 3D-QSAR models and molecular dynamics is consist with the available experimental activities. All the results will facilitate the optimization of this series of FAK inhibitors with higher inhibitory activities. 相似文献
8.
《Journal of Saudi Chemical Society》2021,25(11):101346
BackgroundSrc homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) as a major phosphatase would affect the development of tumors by regulating several cellular processes, and is a significant potential target for cancer treatment.MethodsIn the present work, a series of pyridine derivatives possessing a wide range of inhibitory activity was employed to investigate the structural requirements by developing three dimensional quantitative structure–activity relationship (3D-QSAR) models using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. The results show that CoMFA (R2cv = 0.646, R2pred = 0.5587) and CoMSIA (R2cv = 0.777, R2pred = 0.7131) have excellent stability and predictability. The relationship between the inhibitory activity and structure of the inhibitors was analyzed by the derived contour maps. Furthermore, the QSAR models were validated by molecular docking and molecular dynamics simulations, which were also applied to reveal the potential molecular mechanism of these inhibitors.FindingsIt was found that Arg110, Asn216, Thr218, Thr252 and Pro490 play a crucial role in stabilizing the inhibitors. Additionally, MM/PBSA calculations provided the binding free energy were also conducted to explain the discrepancy of binding activities. Overall, the outcomes of this work could provide useful information and theoretical guidance for the development of novel and potent SHP2 inhibitors. 相似文献
9.
In order to investigate the inhibiting mechanism and obtain some helpful information for de-signing functional inhibitors against Wee1, three-dimensional quantitative structure-activity relationship (3D-QSAR) and docking studies have been performed on 45 pyrido[2,3-d] pyrim-idine derivatives acting as Wee1 inhibitors. Two optimal 3D-QSAR models with significant statistical quality and satisfactory predictive ability were established, including the CoMFA model (q2=0.707, R2=0.964) and CoMSIA model (q2=0.645, R2=0.972). The external val-idation indicated that both CoMFA and CoMSIA models were quite robust and had high predictive power with the predictive correlation coefficient values of 0.707 and 0.794, essen-tial parameter r2m values of 0.792 and 0.826, the leave-one-out r2m(LOO) values of 0.781 and 0.809, r2m(overall) values of 0.787 and 0.810, respectively. Moreover, the appropriate binding orientations and conformations of these compounds interacting with Wee1 were revealed by the docking studies. Based on the CoMFA and CoMSIA contour maps and docking analyses, several key structural requirements of these compounds responsible for inhibitory activity were identified as follows: simultaneously introducing high electropositive groups to the sub-stituents R1 and R5 may increase the activity, the substituent R2 should be smaller bulky and higher electronegative, moderate-size and strong electron-withdrawing groups for the substituent R3 is advantageous to the activity, but the substituent X should be medium-size and hydrophilic. These theoretical results help to understand the action mechanism and design novel potential Wee1 inhibitors. 相似文献
10.
Kulkarni RG Srivani P Achaiah G Sastry GN 《Journal of computer-aided molecular design》2007,21(4):155-166
The p38 protein kinase is a serine–threonine mitogen activated protein kinase, which plays an important role in inflammation
and arthritis. A combined study of 3D-QSAR and molecular docking has been undertaken to explore the structural insights of
pyrazolyl urea p38 kinase inhibitors. The 3D-QSAR studies involved comparative molecular field analysis (CoMFA) and comparative
molecular similarity indices (CoMSIA). The best CoMFA model was derived from the atom fit alignment with a cross-validated
r
2 (q
2) value of 0.516 and conventional r
2 of 0.950, while the best CoMSIA model yielded a q
2 of 0.455 and r
2 of 0.979 (39 molecules in training set, 9 molecules in test set). The CoMFA and CoMSIA contour maps generated from these
models provided inklings about the influence of interactive molecular fields in the space on the activity. GOLD, Sybyl (FlexX)
and AutoDock docking protocols were exercised to explore the protein–inhibitor interactions. The integration of 3D-QSAR and
molecular docking has proffered essential structural features of pyrazolyl urea inhibitors and also strategies to design new
potent analogues with enhanced activity. 相似文献
11.
Lan P Xie MQ Yao YM Chen WN Chen WM 《Journal of computer-aided molecular design》2010,24(12):993-1008
Fructose-1,6-biphophatase has been regarded as a novel therapeutic target for the treatment of type 2 diabetes mellitus (T2DM).
3D-QSAR and docking studies were performed on a series of [5-(4-amino-1H-benzoimidazol-2-yl)-furan-2-yl]-phosphonic acid derivatives as fructose-1,6-biphophatase inhibitors. The CoMFA and CoMSIA
models using thirty-seven molecules in the training set gave r
cv2 values of 0.614 and 0.598, r
2 values of 0.950 and 0.928, respectively. The external validation indicated that our CoMFA and CoMSIA models possessed high
predictive powers with r
02 values of 0.994 and 0.994, r
m2 values of 0.751 and 0.690, respectively. Molecular docking studies revealed that a phosphonic group was essential for binding
to the receptor, and some key features were also identified. A set of forty 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
12.
CRTh2 receptor is an important mediator of inflammatory effects and has attracted much attention as a therapeutic target for the treatment of conditions such as asthma, COPD, allergic rhinitis and atopic dermatitis. In pursuit of better CRTh2 receptor antagonist agents, 3D-QSAR studies were performed on a series of 2-(2-(benzylthio)-1H-benzo[d]imidazol-1-yl) acetic acids. There is no crystal structure information available on this protein; hence in this work, ligand-based comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed by atom by atom matching alignment using systematic search and simulated annealing methods. The 3D-QSAR models were generated with 10 different combinations of test and training set molecules, since the robustness and predictive ability of the model is very important. We have generated 20 models for CoMFA and 100 models for CoMSIA based on two different alignments. Each model was validated with statistical cut off values such as q2 > 0.4, r2 > 0.5 and r2pred > 0.5. Based on better q2 and r2pred values, the best predictions were obtained for the CoMFA (model 5 q2 = 0.488, r2pred = 0.732), and CoMSIA (model 45 q2 = 0.525, r2pred = 0.883) from systematic search conformation alignment. The high correlation between the cross-validated/predicted and experimental activities of a test set revealed that the CoMFA and CoMSIA models were robust. Statistical parameters from the generated QSAR models indicated the data is well fitted and have high predictive ability. The generated models suggest that steric, electrostatic, hydrophobic, H-bond donor and acceptor parameters are important for activity. Our study serves as a guide for further experimental investigations on the synthesis of new CRTh2 antagonist. 相似文献
13.
Abstract This study has investigated docking-based 3D quantitative structure–activity relationships (QSARs) for a range of quinoline carboxylic acid derivatives by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). A docking study has shown that most of the compounds formed H-bonds with Arg136 and Gln47, which have already been shown to be essential for the binding of ligands at the active site of the hydroorotate dehydrogenase adenovirus (hDHODH). Bioactive conformations of all the molecules obtained from the docking study were used for the 3D QSAR study. The best CoMFA and CoMSIA models were obtained for the training set and were found to be statistically significant, with cross-validated coefficients (q2 ) of 0.672 and 0.613, r2 cv of 0.635 and 0.598 and coefficients of determination (r2 ) of 0.963 and 0.896, respectively. Both models were validated by a test set of 15 compounds, giving satisfactory predicted correlation coefficients (r2 pred) of 0.824 and 0.793 for the CoMFA and CoMSIA models, respectively. From the docking-based 3D QSAR study we designed 34 novel quinoline-based compounds and performed structure-based virtual screening. Finally, in silico pharmacokinetics and toxicities were predicted for 24 of the best docked molecules. The study provides valuable information for the understanding of interactions between hDHODH and the novel compounds. 相似文献
14.
15.
mTOR has become a promising target for many types of cancer like breast, lung and renal cell carcinoma. CoMFA, CoMSIA, Topomer CoMFA and HQSAR were performed on the series of 39 triazine morpholino derivatives. CoMFA analysis showed q2 value of 0.735, r2cv value of 0.722 and r2pred value of 0.769. CoMSIA analysis (SEHD) showed q2 value of 0.761, r2cv value of 0.775 and r2pred value of 0.651. Topomer CoMFA analysis showed q2 value of 0.693, r2 (conventional correlation coefficient) value of 0.940 and r2pred value of 0.720. HQSAR analysis showed q2,r2and r2pred values of 0.694, 0.920 and 0.750, respectively. HQSAR analysis with the combination of atomic number (A), bond type (B) and atomic connections showed q2 and r2 values of 0.655 and 0.891, respectively. Contour maps from all studies provided significant insights. Molecular docking studies with molecular dynamics simulations were carried out on the highly potent compound 36. Furthermore, four acridine derivatives were designed and docking results of these designed compounds showed the same interactions as that of the standard PI-103 which proved the efficiency of 3D-QSAR and MD/MS study. In future, this study might be useful prior to synthesis for the designing of novel mTOR inhibitors. 相似文献
16.
Yan-Feng Zhang Yi Ma Zhi-Xian Gao Shu-Gui Dai 《Analytical and bioanalytical chemistry》2010,397(6):2551-2557
Immunoassays have been regarded as a possible alternative or supplement for measuring polycyclic aromatic hydrocarbons (PAHs)
in the environment. Since there are too many potential cross-reactants for PAH immunoassays, it is difficult to determine
all the cross-reactivities (CRs) by experimental tests. The relationship between CR and the physical-chemical properties of
PAHs and related compounds was investigated using the CR data from a commercial enzyme-linked immunosorbent assay (ELISA)
kit test. Two quantitative structure-activity relationship (QSAR) techniques, regression analysis and comparative molecular
field analysis (CoMFA), were applied for predicting the CR of PAHs in this ELISA kit. Parabolic regression indicates that
the CRs are significantly correlated with the logarithm of the partition coefficient for the octanol-water system (log K
ow) (r
2 = 0.643, n = 23, P < 0.0001), suggesting that hydrophobic interactions play an important role in the antigen-antibody binding and the cross-reactions
in this ELISA test. The CoMFA model obtained shows that the CRs of the PAHs are correlated with the 3D structure of the molecules
(r
cv
2 = 0.663, r
2 = 0.873, F
4,32 = 55.086). The contributions of the steric and electrostatic fields to CR were 40.4 and 59.6%, respectively. Both of the
QSAR models satisfactorily predict the CR in this PAH immunoassay kit, and help in understanding the mechanisms of antigen-antibody
interaction. 相似文献
17.
Summary Molecular docking and 3D-QSAR studies were performed to determine the binding mode for a series of benzoxazine oxytocin antagonists
taken from the literature. Structural hypotheses were generated by docking the most active molecule to the rigid receptor
by means of AutoDock 3.05. The cluster analysis yielded seven possible binding conformations. These structures were refined
by using constrained simulated annealing, and the further ligands were aligned in the refined receptor by molecular docking.
A good correlation was found between the estimated ΔGbind and the pKi values for complex F. The Connolly-surface analysis, CoMFA and CoMSIA models qCoMFA2 = 0.653, qCoMSA2 = 0.630 and rpred,CoMFA2 = 0.852 , rpred,CoMSIA2 = 0.815) confirmed the scoring function results. The structural features of the receptor–ligand complex and the CoMFA and
CoMSIA fields are in closely connected. These results suggest that receptor–ligand complex F is the most likely binding hypothesis
for the studied benzoxazine analogs. 相似文献
18.
Jae Yoon Chung Hwan Won Chung Seung Joo Cho Jung-Mi Hah Art E. Cho 《Journal of computer-aided molecular design》2010,24(5):385-397
Three dimensional (3D) quantitative structure-activity relationship studies of 37 B-Raf inhibitors, pyrazole-based derivatives,
were performed. Based on the co-crystallized compound (PDB ID: 3D4Q), several alignment methods were utilized to derive reliable
comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models. Receptor-guided
alignment with quantum mechanics/molecular mechanics (QM/MM) minimization led to the best CoMFA model (q
2 = 0.624, r
2 = 0.959). With the same alignment, a statistically reliable CoMSIA model with steric, H-bond acceptor, and hydrophobic fields
was also derived (q
2 = 0.590, r
2 = 0.922). Both models were validated with an external test set, which gave satisfactory predictive r
2 values of 0.926 and 0.878, respectively. Contour maps from CoMFA and CoMSIA models revealed important structural features
responsible for increasing biological activity within the active site and explained the correlation between biological activity
and receptor-ligand interactions. New fragments were identified as building blocks which can replace R1-3 groups through combinatorial
screening methods. By combining these fragments a compound with a high bioactivity level prediction was found. These results
can offer useful information for the design of new B-Raf inhibitors. 相似文献
19.
1,2-萘醌类化合物抑制PTP1B的三维定量构效关系研究 总被引:1,自引:1,他引:0
蛋白酪氨酸磷酸酶1B (protein tyrosine phosphatase 1B, PTP-1B)是近年来发现的治疗II型糖尿病的新靶点, 1,2-萘醌类化合物对PTP-1B有较好的抑制活性, 具有良好的药用前景. 为了设计出本类化合物抑制效果更好的分子构型, 用比较分子力场分析(CoMFA)和比较分子相似性指数分析(CoMSIA)对该类化合物进行了三维定量构效关系(3D-QSAR)的研究, 并建立了相关的预测模型. 其中, CoMFA模型的交叉验证相关系数(q2)为0.555, 非交叉验证相关系数(r2)为0.991, 标准偏差(SEE)为0.049, F值为564.910. CoMSIA模型的q2为0.558, r2为0.991, SEE为0.050, F值为542.773. 计算结果表明, 获得的CoMFA和CoMSIA模型具有良好的预测能力, 可以应用于指导该类化合物的设计. 相似文献