共查询到20条相似文献,搜索用时 31 毫秒
1.
Durdagi S Mavromoustakos T Papadopoulos MG 《Bioorganic & medicinal chemistry letters》2008,18(23):6283-6289
For the first time, a set of experimentally reported [60] fullerene derivatives were subjected to the 3D-QSAR/CoMFA and CoMSIA studies. The aim of this study is to propose a series of novel [60] fullerene-based inhibitors with optimal binding affinity for the HIV-1 PR enzyme. The position of the template molecule at the cavity of HIV-1 PR was optimized and 3D QSAR models were developed. Relative contributions of steric/electrostatic fields of the 3D-QSAR/CoMFA and CoMSIA models have shown that steric effects govern the bioactivity of the compounds, but electrostatic interactions play also an important role.The de novo drug design Leapfrog simulations provided a series of novel compounds with predicted improved inhibition effect. 相似文献
2.
In the current study, the applicability and scope of 3D-QSAR models (CoMFA and CoMSIA) to complement virtual screening using
3D pharmacophore and molecular docking is examined and applied to identify potential hits against Mycobacterium tuberculosis Enoyl acyl carrier protein reductase (MtENR). Initially CoMFA and CoMSIA models were developed using series of structurally
related arylamides as MtENR inhibitors. Docking studies were employed to position the inhibitors into MtENR active site to
derive receptor based 3D-QSAR models. Both CoMFA and CoMSIA yielded significant cross validated q2 values of 0.663 and 0.639 and r2 values of 0.989 and 0.963, respectively. The statistically significant models were validated by a test set of eight compounds
with predictive r2 value of 0.882 and 0.875 for CoMFA and CoMSIA. The contour maps from 3D-QSAR models in combination with docked binding structures
help to better interpret the structure activity relationship. Integrated with CoMFA and CoMSIA predictive models structure
based (3D-pharmacophore and molecular docking) virtual screening have been employed to explore potential hits against MtENR.
A representative set of 20 compounds with high predicted IC50 values were sorted out in the present study. 相似文献
3.
Yan-Ke Jiang 《Journal of molecular modeling》2010,16(7):1239-1249
Three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular docking studies were carried out to
explore the binding of 73 inhibitors to dipeptidyl peptidase IV (DPP-IV), and to construct highly predictive 3D-QSAR models
using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The negative
logarithm of IC50 (pIC50) was used as the biological activity in the 3D-QSAR study. The CoMFA model was developed by steric and electrostatic field
methods, and leave-one-out cross-validated partial least squares analysis yielded a cross-validated value (rcv2 {\hbox{r}}_{{\rm{cv}}}^{\rm{2}} ) of 0.759. Three CoMSIA models developed by different combinations of steric, electrostatic, hydrophobic and hydrogen-bond
fields yielded significant rcv2 {\hbox{r}}_{{\rm{cv}}}^{\rm{2}} values of 0.750, 0.708 and 0.694, respectively. The CoMFA and CoMSIA models were validated by a structurally diversified
test set of 18 compounds. All of the test compounds were predicted accurately using these models. The mean and standard deviation
of prediction errors were within 0.33 and 0.26 for all models. Analysis of CoMFA and CoMSIA contour maps helped identify the
structural requirements of inhibitors, with implications for the design of the next generation of DPP-IV inhibitors for the
treatment of type 2 diabetes. 相似文献
4.
5.
Multiple receptors conformation docking (MRCD) and clustering of dock poses allows seamless incorporation of receptor binding
conformation of the molecules on wide range of ligands with varied structural scaffold. The accuracy of the approach was tested
on a set of 120 cyclic urea molecules having HIV-1 protease inhibitory activity using 12 high resolution X-ray crystal structures
and one NMR resolved conformation of HIV-1 protease extracted from protein data bank. A cross validation was performed on
25 non-cyclic urea HIV-1 protease inhibitor having varied structures. The comparative molecular field analysis (CoMFA) and
comparative molecular similarity indices analysis (CoMSIA) models were generated using 60 molecules in the training set by
applying leave one out cross validation method, rloo2 values of 0.598 and 0.674 for CoMFA and CoMSIA respectively and non-cross validated regression coefficient r2 values of 0.983 and 0.985 were obtained for CoMFA and CoMSIA respectively. The predictive ability of these models was determined
using a test set of 60 cyclic urea molecules that gave predictive correlation (rpred2) of 0.684 and 0.64 respectively for CoMFA and CoMSIA indicating good internal predictive ability. Based on this information
25 non-cyclic urea molecules were taken as a test set to check the external predictive ability of these models. This gave
remarkable out come with rpred2 of 0.61 and 0.53 for CoMFA and CoMSIA respectively. The results invariably show that this method is useful for performing
3D QSAR analysis on molecules having different structural motifs. 相似文献
6.
《Bioorganic & medicinal chemistry》2016,24(2):73-84
In this work, 48 thrombin inhibitors based on the structural scaffold of dabigatran were analyzed using a combination of molecular modeling techniques. We generated three-dimensional quantitative structure–activity relationship (3D-QSAR) models based on three alignments for both comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) to highlight the structural requirements for thrombin protein inhibition. In addition to the 3D-QSAR study, Topomer CoMFA model also was established with a higher leave-one-out cross-validation q2 and a non-cross-validation r2, which suggest that the three models have good predictive ability. The results indicated that the steric, hydrophobic and electrostatic fields play key roles in QSAR model. Furthermore, we employed molecular docking and re-docking simulation explored the binding relationship of the ligand and the receptor protein in detail. Molecular docking simulations identified several key interactions that were also indicated through 3D-QSAR analysis. On the basis of the obtained results, two compounds were designed and predicted by three models, the biological evaluation in vitro (IC50) demonstrated that these molecular models were effective for the development of novel potent thrombin inhibitors. 相似文献
7.
Vascular endothselial growth factor (VEGF) and its receptor tyrosine kinase VEGFR-2 or kinase insert domain receptor (KDR)
have been identified as new promising targets for the design of novel anticancer agents. It is reported that 4-(1H-indazol-4-yl)phenylamino and aminopyrazolopyridine urea derivatives exhibit potent inhibitory activities toward KDR. To investigate
how their chemical structures relate to the inhibitory activities and to identify the key structural elements that are required
in the rational design of potential drug candidates of this class, molecular docking simulations and three-dimensional quantitative
structure-activity relationship (3D-QSAR) methods were performed on 78 4-(1H-indazol-4-yl)phenylamino and aminopyrazolopyridine urea derivatives as KDR inhibitors. Surflex-dock was used to determine
the probable binding conformations of all the compounds at the active site of KDR. As a result, multiple hydrophobic and hydrogen-bonding
interactions were found to be two predominant factors that may be used to modulate the inhibitory activities. Comparative
molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) 3D-QSAR models were developed
based on the docking conformations. The CoMFA model produced statistically significant results with the cross-validated correlation
coefficient q2 of 0.504 and the non-cross-validated correlation coefficient r2 of 0.913. The best CoMSIA model was obtained from the combination of steric, electrostatic and hydrophobic fields. Its q2 and r2 being 0.595 and 0.947, respectively, indicated that it had higher predictive ability than the CoMFA model. The predictive
abilities of the two models were further validated by 14 test compounds, giving the predicted correction coefficients rpred2 of 0.727 for CoMFA and 0.624 for CoMSIA, respectively. In addition, the CoMFA and CoMSIA models were used to guide the design
of a series of new inhibitors of this class with predicted excellent activities. Thus, these models may be used as an efficient
tool to predict the inhibitory activities and to guide the future rational design of 4-(1H-indazol-4-yl)phenylamino and aminopyrazolopyridine urea derivatives-based novel KDR inhibitors with potent activities. 相似文献
8.
9.
The Aurora kinases have been regarded as attractive targets for the development of new anticancer agents. Recently a series
of azaindole derivatives with Aurora B inhibitory activities were reported. To explore the relationship between the structures
of substituted azaindole derivatives and their inhibition of Aurora B, 3D-QSAR and molecular docking studies were performed
on a dataset of 41 compounds. 3D-QSAR, including CoMFA and CoMSIA, were applied to identify the key structures impacting their
inhibitory potencies. The CoMSIA model showed better results than CoMFA, with r
2
cv value of 0.575 and r
2
value of 0.987. 3D contour maps generated from CoMFA and CoMSIA along with the docking binding structures provided enough
information about the structural requirements for better activity. Based on the structure-activity relationship revealed by
the present study, we have designed a set of novel Aurora B inhibitors that showed excellent potencies in the developed models.
Thus, our results allowed us to design new derivatives with desired activities. 相似文献
10.
Novel anti-HIV-1 agents derived from betulinic acid have been greatly concerned. 3D-QSAR and molecular docking studies were
applied to rationalize the structural requirements responsible for the anti-HIV activity of these compounds. The CoMFA and
CoMSIA models resulted from 28 molecules gave r
cv2 values of 0.599 and 0.630, r
2
values of 0.994 and 0.958, respectively. To estimate the predictive ability of the 3D-QSAR model, an external validation
was employed. Based on the contour maps generated from both CoMFA and CoMSIA, we have identified some key features in the
betulinic acid derivatives that are responsible for the anti-HIV activity. Molecular docking was used to explore the binding
mode between these derivatives and HIV gp120. We have therefore designed a series of novel betulinic acid derivatives by utilizing
the SAR results revealed in the present study, which were predicted with excellent potencies in the developed models. The
results provide a valuable method to design new betulinic acid derivatives as anti-HIV-1 agents. 相似文献
11.
Potshangbam AM Tanneeru K Reddy BM Guruprasad L 《Bioorganic & medicinal chemistry letters》2011,21(23):7219-7223
The three dimensional-quantitative structure activity relationship (3D-QSAR) studies were performed on a series of falcipain-3 inhibitors using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. A training set containing 42 molecules served to establish the QSAR models. The optimum CoMFA and CoMSIA models obtained for the training set were statistically significant with cross-validated correlation coefficients r(cv)(2) (q(2)) of 0.549 and 0.608, and conventional correlation coefficients (r(2)) of 0.976 and 0.932, respectively. An independent test set of 12 molecules validated the external predictive power of both models with predicted correlation coefficients (r(pred)(2)) for CoMFA and CoMSIA as 0.697 and 0.509, respectively. The docking of inhibitors into falcipain-3 active site using GOLD software revealed the vital interactions and binding conformation of the inhibitors. The CoMFA and CoMSIA field contour maps agree well with the structural characteristics of the binding pocket of falcipain-3 active site, which suggests that the information rendered by 3D-QSAR models and the docking interactions can provide guidelines for the development of improved falcipain-3 inhibitors. 相似文献
12.
Penghua Li Jiale Peng Yeheng Zhou Yaping Li XingYong Liu 《Journal of receptor and signal transduction research》2018,38(3):213-224
Human Coagulation Factor IXa (FIXa), specifically inhibited at the initiation stage of the blood coagulation cascade, is an excellent target for developing selective and safe anticoagulants. To explore this inhibitory mechanism, 86 FIXa inhibitors were selected to generate pharmacophore models and subsequently SAR models. Both best pharmacophore model and ROC curve were built through the Receptor–Ligand Pharmacophore Generation module. CoMFA model based on molecular docking and PLS factor analysis methods were developed. Model propagations values are q2?=?0.709, r2?=?0.949, and r2pred?=?0.905. The satisfactory q2 value of 0.609, r2 value of 0.962, and r2pred value of 0.819 for CoMSIA indicated that the CoMFA and CoMSIA models are both available to predict the inhibitory activity on FIXa. On the basis of pharmacophore modeling, molecular docking, and 3D-QSAR modeling screening, six molecules are screened as potential FIXa inhibitors. 相似文献
13.
Amirreza Dowlati Beirami Zahra Hajimahdi 《Journal of biomolecular structure & dynamics》2019,37(11):2999-3006
A series of 26 selective COX-2 inhibitors which reported previously by our laboratory was selected to generate three-dimensional quantitative structure activity relationship (3D-QSAR) model. Active conformation of each molecule was predicted by docking studies and used for molecular alignment. Activity of 20 molecules as a train set was predicted using three methods including comparative molecular field analysis (CoMFA), CoMFA region focusing (CoMFA-RG) and comparative molecular similarity index analysis (CoMSIA). The best models of CoMFA-RG and CoMSIA revealed correlation coefficients r2 of 0.955 and 0.947, the leave one out cross-validation coefficients q2 of 0.573 and 0.574, respectively. In addition, CoMFA-RG and CoMSIA models were validated by a test set of six molecules with predicted coefficients r2pred of 0.644 and 0.799, respectively. Contour maps of generated models provided fruitful information about structural aspect of molecules that affected their COX-2 inhibitory activity. Based on three models results, steric and electrostatic properties are the most important factors in controlling the activity of the molecules. Results of CoMFA-RG and CoMSIA models were utilized to design new molecules. Comparison of experimental and predicted pIC50 values of designed molecules indicated that CoMFA-RG had the more predictive ability.
Communicated by Ramaswamy H. Sarma 相似文献
14.
Docking simulations and three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses were conducted on a series of indole amide analogues as potent histone deacetylase inhibitors. The studies include comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Selected ligands were docked into the active site of human HDAC1. Based on the docking results, a novel binding mode of indole amide analogues in the human HDAC1 catalytic core is presented, and enzyme/inhibitor interactions are discussed. The indole amide group is located in the open pocket, and anchored to the protein through a pair of hydrogen bonds with Asp99 O-atom and amide NH group on ligand. Based on the binding mode, predictive 3D-QSAR models were established, which had conventional r2 and cross-validated coefficient values (r(cv)2) up to 0.982 and 0.601 for CoMFA and 0.954 and 0.598 for CoMSIA, respectively. A comparison of the 3D-QSAR field contributions with the structural features of the binding site showed good correlation between the two analyses. The results of 3D-QSAR and docking studies validate each other and provided insight into the structural requirements for activity of this class of molecules as HDAC inhibitors. The CoMFA and CoMSIA PLS contour maps and MOLCAD-generated active site electrostatic, lipophilicity, and hydrogen-bonding potential surface maps, as well as the docking studies, provided good insights into inhibitor-HDAC interactions at the molecular level. Based on these results, novel molecules with improved activity can be designed. 相似文献
15.
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
16.
Aurora-A, the most widely studied isoform of Aurora kinase overexpressed aberrantly in a wide variety of tumors, has been
implicated in early mitotic entry, degradation of natural tumor suppressor p53 and centrosome maturation and separation; hence,
potent inhibitors of Aurora-A may be therapeutically useful drugs in the treatment of various forms of cancer. Here, we report
an in silico study on a group of 220 reported Aurora-A inhibitors with six different substructures. Three-dimensional quantitative
structure–activity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and
comparative molecular similarity indices analysis (CoMSIA) techniques on this series of molecules. The resultant optimum 3D-QSAR
models exhibited an r
cv2 value of 0.404-0.582 and their predictive ability was validated using an independent test set, ending in r
pred2 0.512-0.985. In addition, docking studies were employed to explore these protein–inhibitor interactions at the molecular
level. The results of 3D-QSAR and docking analyses validated each other, and the key structural requirements affecting Aurora-A
inhibitory activities, and the influential amino acids involved were identified. To the best of our knowledge, this is the
first report on 3D-QSAR modeling of Aurora-A inhibitors, and the results can be used to accurately predict the binding affinity
of related analogues and also facilitate the rational design of novel inhibitors with more potent biological activities. 相似文献
17.
M. Muddassar F. A. Pasha M. M. Neaz Y. Saleem S. J. Cho 《Journal of molecular modeling》2009,15(2):183-192
Protein kinase B (PKB; also known as Akt kinase) is located downstream in the PI-3 kinase pathway. Overexpression and constitutive
activation of PKB/Akt leads to human prostate, breast and ovarian carcinomas. A series of 69 PKB/Akt inhibitors were examined
to explore their binding modes using FlexX, and three-dimensional quantitative structure–activity relationship (3D-QSAR) studies
based on comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were
performed to provide structural insights into these compounds. CoMFA produced statistically significant results, with cross-validated
q
2
and non-cross validated correlation r
2
coefficients of 0.53 and 0.95, respectively. For CoMSIA, steric, hydrophobic and hydrogen bond acceptor fields jointly yielded
‘leave one out’ q
2
= 0.51 and r
2
= 0.84. The predictive power of CoMFA and CoMSIA was determined using a test set of 13 molecules, which gave correlation
coefficients, of 0.58 and 0.62, respectively. Molecular docking revealed that the binding modes of these molecules in the ATP binding sites
of the Akt kinase domain were very similar to those of the co-crystallized ligand. The information obtained from 3D contour
maps will allow the design of more potent and selective Akt kinase inhibitors. 相似文献
18.
Inhibition of the protein chaperone Hsp90α is a promising approach for cancer therapy. In this work, a molecular modeling
study combining pharmacophore model, molecular docking and three-dimensional quantitative structure-activity relationships
(3D-QSAR) was performed to investigate a series of pyrazole/isoxazole scaffold inhibitors of human Hsp90α. The pharmacophore
model can provide the essential features required for the biological activities of the inhibitors. The molecular docking study
can give insight into the binding mode between Hsp90α and its inhibitors. 3D-QSAR based on CoMFA and CoMSIA models were performed
from three different strategies for conformational selection and alignment. The receptor-based models gave the most statistically
significant results with cross-validated q
2 values of 0.782 and 0.829 and r
2 values of 0.909 and 0.968, for CoMFA and CoMSIA respectively. Furthermore, the 3D contour maps superimposed within the binding
site of Hsp90α could help to understand the pivotal interaction and the structural requirements for potent Hsp90α inhibitors.
The results show 4-position of pyrazole/isoxazole ring requires bulky and hydrophobic groups, and bulky and electron repulsion
substituent of 5-amides is favorable for enhancing activity. This study will be helpful for the rational design of new potent
Hsp90α inhibitors. 相似文献
19.
Seventy-five 1,5,6,7-tetrahydro-pyrrolo[3,2-C]pyridinone derivatives displaying potent activities against Cdc7 kinase were
selected to establish 3D-QSAR models using CoMFA and CoMSIA methods. Internal and external cross-validation techniques were
investigated as well as some measures including region focusing, progressive scrambling, bootstraping and leave-group-out.
The satisfactory CoMFA model predicted a q
2 value of 0.836 and an r
2 value of 0.950, indicating that electrostatic and steric properties play a significant role in potency. The best CoMSIA model,
based on a combination of steric, electrostatic and H-bond acceptor effects, predicted a q
2 value of 0.636 and an r
2 value of 0.907. The models were graphically interpreted using contour plots which provided insight into the structural requirements
for increasing the activity of a compound. The final 3D-QSAR results could be used for rational design of potent inhibitors
against Cdc7 kinase. 相似文献
20.
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