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1.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(3):339-347
Pharmacophore modelling and atom-based 3D-QSAR studies were carried out for a series of compounds belonging to N-methyl pyrimidones as HIV-1 integrase inhibitors. Based on the ligand-based pharmacophore model, we got 5-point pharmacophore model AADDR, with two hydrogen bond acceptors (A), two hydrogen bond donors (D) and one aromatic ring (R). The generated pharmacophore-based alignment was used to derive a predictive atom-based 3D-QSAR model for the training set (r2?=?0.92, SD?=?0.16, F?=?84.8, N?=?40) and for test set (Q2?=?0.71, RMSE?=?0.06, Pearson R?=?0.90, N?=?10). From these results, AADDR pharmacophore feature was selected as best common pharmacophore hypothesis, and atom-based 3D-QSAR results also support the outcome by means of favourable and unfavourable regions of hydrophobic and electron-withdrawing groups for the most potent compound 30. These results can be useful for further design of new and potent HIV-1 IN inhibitors. 相似文献
2.
As a tumor suppressor, p53 protein regulates the cell cycle and is involved in preventing tumorgenesis. The protein level
of p53 is under the tight control of its negative regulator human double minute 2 (HDM2) via ubiquitination. Therefore, the design of inhibitors of HDM2 has attracted much interest of research on developing novel anticancer drugs. Presently, two classes of molecules, i.e.,
the 1,4-benzodiazepine-2,5-diones (BDPs) and N-Acylpolyamine (NAPA) derivatives were studied by three-dimensional quantitative
structure–activity relationship (3D-QSAR) modeling approaches including the comparative molecular field analysis (CoMFA) and
comparative molecular similarity index analysis (CoMSIA) as promising p53-HDM2 inhibitors. Based on both the ligand-based and receptor-guided (docking) alignments, two optimal 3D-QSAR models were obtained
with good predictive power of q
2 = 0.41, r
2
pred = 0.60 for BDPs, and q
2 = 0.414, r
2
pred = 0.69 for NAPA analogs, respectively. By analysis of the model and its related contour maps, it is revealed that the electrostatic
interactions contributed much larger to the compound binding affinity than the steric effects. And the contour maps intuitively
suggested where to modify the molecular structures in order to improve the binding affinity. In addition, molecular dynamics
simulation (MD) study was also carried out on the dataset with purpose of exploring the detailed binding modes of ligand in
the HDM2 binding pocket. Based on the CoMFA contour maps and MD-based docking analyses, some key structural aspects responsible for
inhibitory activity of these two classes of compounds were concluded as follows: For BDPs, the R1 and R3 regions should have small electronegativity groups; substituents R2 and R4 should be larger, and R3 substituent mainly involves in H-bonds forming. For NAPA derivatives, bulky and electropositive groups in ring B and ring
A, small substituent at region P is favorable for the inhibitory activity. The models and related information, we hope, may
provide important insight into the inhibitor-p53-HDM2 interactions and be helpful for facilitating the design of novel potent inhibitors. 相似文献
3.
Predictive pharmacophore models have been developed for a series of arylamino-substituted benzo[b]thiophenes exhibiting free
radical scavenging activity. 3D pharmacophore models were generated using a set of 20 training set compounds and subsequently
validated by mapping 6 test set compounds using Discovery Studio 2.1 software. Further model validation was performed by randomizing
the data using Fischer’s validation technique at the 95% confidence level. The most predictive pharmacophore model developed
using the conformers obtained from the BEST method showed a correlation coefficient (r) of 0.942 and consisted of three features: hydrogen bond donor, hydrogen bond acceptor and aromatic ring. Acceptable values
of external validation parameters, like Rpred2 R_{{\rm{pred}}}^2 (0.853) and rm( test )2 r_{m\left( {test} \right)}^2 (0.844), also implied that the external predictivity of the model was significant. The development of further pharmacophore
models using conformers obtained from the FAST method yielded a few models with good predictivity, with the best one (r = 0.904) consisting of two features: hydrogen bond donor and hydrogen bond acceptor. Significant values of external validation
parameters, Rpred2 R_{{\rm{pred}}}^2 (0.913) and rm( test )2 r_{m\left( {test} \right)}^2 (0.821), also reflect the high predictive ability of the model. Again, Fischer validation results implied that the models
developed were robust enough and their good results were not based on mere chance. These validation approaches indicate the
reliability of the predictive abilities of the 3D pharmacophore models developed here, which may thus be further utilized
as a 3D query tool in the virtual screening of new chemical entities with potent antioxidant activities. 相似文献
4.
5.
Partha Pratim Roy 《Molecular simulation》2013,39(11):887-905
Pharmacophore mapping, molecular docking and quantitative structure–activity relationship (QSAR) studies were carried out for a structurally diverse set of 48 compounds as CYP2B6 inhibitors. The generated best pharmacophore hypotheses from the three methods of conformer generation (FAST, BEST and conformer algorithm based on energy screening and recursive buildup) indicate the importance of two features, namely, hydrogen bond acceptor [electron-rich centre] and ring aromaticity. The distance between the two centres of the important features for ideal inhibitors varied from 5.82 to 6.03 Å. The chemometric tools used for the QSAR analysis were genetic function approximation (GFA) and genetic partial least squares. The developed QSAR models indicate the importance of an electron-rich centre, size of molecule, impact of branching and ring system and distribution of charges in the molecular surface. The docking study confirms the importance of an electron-rich centre for binding with the iron atom of the cytochrome enzyme. A GFA model with spline option was found to be the best model based on internal validation as well as the r 2 m (overall) criterion (Q 2 = 0.772, r 2 m (overall) = 0.774). According to the external prediction statistics (R 2 pred = 0.876), another GFA-derived model with spline option outperforms the remaining models. 相似文献
6.
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
7.
Srilata Ballu Ramesh Itteboina Sree Kanth Sivan 《Journal of receptor and signal transduction research》2018,38(1):61-70
Filamentous temperature-sensitive protein Z (FtsZ) is a protein encoded by the FtsZ gene that assembles into a Z-ring at the future site of the septum of bacterial cell division. Structurally, FtsZ is a homolog of eukaryotic tubulin but has low sequence similarity; this makes it possible to obtain FtsZ inhibitors without affecting the eukaryotic cell division. Computational studies were performed on a series of substituted 3-arylalkoxybenzamide derivatives reported as inhibitors of FtsZ activity in Staphylococcus aureus. Quantitative structure-activity relationship models (QSAR) models generated showed good statistical reliability, which is evident from r2ncv and r2loo values. The predictive ability of these models was determined and an acceptable predictive correlation (r2Pred) values were obtained. Finally, we performed molecular dynamics simulations in order to examine the stability of protein-ligand interactions. This facilitated us to compare free binding energies of cocrystal ligand and newly designed molecule B1. The good concordance between the docking results and comparative molecular field analysis (CoMFA)/comparative molecular similarity indices analysis (CoMSIA) contour maps afforded obliging clues for the rational modification of molecules to design more potent FtsZ inhibitors. 相似文献
8.
9.
Xiaohong Zhu Liangliang Zhong Duoqian Dai Meiyuan Hong Rong You 《Molecular simulation》2017,43(7):534-547
AbstractThe p90 ribosomal s6 kinase 2 (RSK2) is a promising target because of its over expression and activation in human cancer cells and tissues. Over the last few years, significant efforts have been made in order to develop RSK2 inhibitors to treat myeloma, prostatic cancer, skin cancer and etc., but with limited success so far. In this paper, pharmacophore modelling, molecular docking study and molecular dynamics (MD) simulation have been performed to explore the novel inhibitors of RSK2. Pharmacophore models were developed by 95 molecules having pIC50 ranging from 4.577 to 9.000. The pharmacophore model includes one hydrogen bond acceptor (A), one hydrogen bond donor (D), one hydrophobic feature (H) and one aromatic ring (R). It is the best pharmacophore hypothesis that has the highest correlation coefficient (R2 = 0.91) and cross validation coefficient (Q2 = 0.71) at 5 component PLS factor. It was evaluated using enrichment analysis and the best model was used for virtual screening. The constraints used in this study were docking score, ADME properties, binding free energy estimates and IFD Score to screen the database. Ultimately, 12 hits were identified as potent and novel RSK2 inhibitors. A 15 ns molecular dynamics (MD) simulation was further employed to validate the reliability of the docking results. 相似文献
10.
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
11.
Fereshteh Shiri Maryam Salahinejad Rahmatollah Dijoor Massoud Nejati-Yazdinejad 《Journal of receptor and signal transduction research》2018,38(2):151-165
Pathogenic Gram-negative bacteria are responsible for nearly half of the serious human infections. Hologram quantitative structure–activity relationships (HQSAR), comparative molecular field analysis (CoMFA), and comparative molecular similarity index analysis (CoMSIA) were implemented on a group of 32 of potent Gram-negative LpxC inhibitors. The most effective HQSAR model was obtained using atoms, bonds, donor, and acceptor as fragment distinction. The cross-validated correlation coefficient (q2), non-cross-validated correlation coefficient (r2), and predictive correlation coefficient (r2Pred) for test set of HQSAR model were 0.937, 0.993, and 0.892, respectively. The generated models were found to be statistically significant as the CoMFA model had (r2?=?0.967, q2?=?0.804, r2Pred?=?0.827); the CoMSIA model had (r2?=?0.963, q2?=?0.752, r2Pred?=?0.857). Molecular docking was employed to validate the results of the HQSAR, CoMFA, and CoMSIA models. Based on the obtained information, six new LpxC inhibitors have been designed. 相似文献
12.
The interaction between puerarin and β-cyclodextrin (CD) has been studied in D2O, H2O/acetone-d
6, acetone-d
6 and DMSO-d
6 solutions by 1H NMR spectroscopy. The NMR data obtained from hydroxy protons indicate that the formation of the inclusion complex between
the two molecules is not stabilized by strong hydrogen bond interactions. The sugar part of puerarin as well as the A ring
are outside the β-CD cavity while the B and C rings are located inside the cavity and the interaction is mainly stabilized by hydrophobic interactions.
In DMSO at 30°C and in acetone-d
6/H2O at temperature below −5°C, doubling of some signals indicated that, in these solvent systems, free rotation of the C-glycosyl
bond was restricted due to the steric hindrance between the phenolic hydroxy group at C-7 and the bulky sugar moiety at C-8.
In acetone, fast exchange of phenolic protons on the NMR timescale was observed, showing the effect of the solvent on the
hindered rotation. 相似文献
13.
Molecular docking and pharmacophore model approaches were used to characterise the binding features of four different series of Rho kinase (ROCK) inhibitors. Docking simulation of 20 inhibitors with ROCK was performed. The binding conformations and binding affinities of these inhibitors were obtained using AutoDock 4.0 software. The predicted binding affinities correlate well with the activities of these inhibitors (R 2 = 0.904). 3D pharmacophore models were generated for ROCK based on highly active inhibitors implemented in Catalyst 4.11 program. The best pharmacophore model consists of one hydrogen bond acceptor feature and two hydrophobic features, and they all seemed to be essential for inhibitors in terms of their binding activities. It is anticipated that the findings reported in this paper may provide very useful information for designing new ROCK inhibitors. 相似文献
14.
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
15.
《Journal of receptor and signal transduction research》2013,33(1):3-16
To study the pharmacophore properties of quinazolinone derivatives as 5HT7 inhibitors, 3D QSAR methodologies, namely Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were applied, partial least square (PLS) analysis was performed and QSAR models were generated. The derived model showed good statistical reliability in terms of predicting the 5HT7 inhibitory activity of the quinazolione derivative, based on molecular property fields like steric, electrostatic, hydrophobic, hydrogen bond donor and hydrogen bond acceptor fields. This is evident from statistical parameters like q2 (cross validated correlation coefficient) of 0.642, 0.602 and r2 (conventional correlation coefficient) of 0.937, 0.908 for CoMFA and CoMSIA respectively. The predictive ability of the models to determine 5HT7 antagonistic activity is validated using a test set of 26 molecules that were not included in the training set and the predictive r2 obtained for the test set was 0.512 & 0.541. Further, the results of the derived model are illustrated by means of contour maps, which give an insight into the interaction of the drug with the receptor. The molecular fields so obtained served as the basis for the design of twenty new ligands. In addition, ADME (Adsorption, Distribution, Metabolism and Elimination) have been calculated in order to predict the relevant pharmaceutical properties, and the results are in conformity with required drug like properties. 相似文献
16.
Meng-Nan Jiang Xiao-Ping Zhou Dong-Ru Sun Huan Gao Qing-Chuan Zheng Hong-Xing Zhang 《Journal of biomolecular structure & dynamics》2013,31(14):3705-3717
Transforming growth factor type 1 receptor (ALK5) is kinase associated with a wide variety of pathological processes, and inhibition of ALK5 is a good strategy to treat many kinds of cancer and fibrotic diseases. Recently, a series of compounds have been synthesized as ALK5 inhibitors. However, the study of their selectivity against other potential targets remains elusive. In this research, a data-set of ALK5 inhibitors were collected and studied based on the combination of 2D-QSAR, molecular docking and molecular dynamics simulation. The quality of QSAR models were assessed statistically by F, R2, and R2ADJ, proved to be credible. The cross-validations for the models (q2LOO = 0.571 and 0.629, respectively) showed their robustness, while the external validations (r2test = 0.703 and 0.764, respectively) showed their predictive power. Besides, the predicted binding free energy results calculated by MM/GBSA method were in accordance with the experimental data, and the van der Waals energy term was the factor that had the most significant impact on ligand binding. What is more, several important residues were found to significantly affect the binding affinity. Finally, based on our analyses above, a proposed series of molecules were designed. 相似文献
17.
Mahalakshmi Thillainayagam Kullappan Malathi Anand Anbarasu Harpreet Singh Renu Bahadur 《Journal of biomolecular structure & dynamics》2019,37(12):3168-3182
In the present study, we have explored the anti-malarial potential of epoxyazadiradione, the natural entity extracted from the neem seed oil and its chemical derivatives, against Plasmodium falciparum. The Surflex dock analysis of 41 compounds against an indispensable target, plasmepsin I (PM-I) revealed that around 70% of the compounds are found to have good binding capacity with the consensus score (C-score) of 5 to 4 with few hydrogen bonds. To elucidate the major structural requirements, vital for binding with the plasmepsin enzyme and to develop the predictive models, three-dimentional quantitative structural activity relationship (3D-QSAR) – comparative molecular field analysis (CoMFA) was carried out using Sybyl X.0. Robust and predictive models were obtained with cross-validated correlation coefficient (q2) value of 0.967 and the non-cross-validated correlation coefficient (r2) value of 0.825, which were validated by an external test set with the predictive correlation coefficient r2(pred) values of 0.773. Three zones were identified for substitution with bulky groups and one zone for substitution with non-bulky groups. Three positions favouring the electronegative group substitution and one for the electropositive group substitution were identified. The physicochemical properties of ligands with the highest C-score were studied.
Communicated by Ramaswamy H. Sarma 相似文献
18.
19.
Mao-Feng Sun Shun-Chieh Yang Kai-Wei Chang Tsung-Ying Tsai Hsin-Yi Chen Fuu-Jen Tsai 《Molecular simulation》2013,39(10):884-892
Human epidermal growth factor receptor type 2 (HER2) overexpression, which has been reported to increase the malignancy of human ovarian cancer cells and the metastatic potential of human breast cancer cells, is an important factor in tumour formation and tumour growth. However, currently available HER2 inhibitors, such as Lapatinib, for cancer therapy cause adverse side effects including diarrhoea, rash and possible liver toxicity. We hoped to find novel agents that cause less adverse side effects by performing virtual screening process on the world's largest traditional Chinese medicine compound database. The results thus obtained were then validated using 3D quantitative structure–activity relationship model. Top three candidates were selected from the docking results. The top three candidates and the control both formed a hydrogen bond with the key residue, Lys724. This showed that the candidates and the control have similar binding effects to HER2. These candidates were investigated using comparative molecular field analysis and comparative molecular similarity indices analysis models. The results from these models showed high correlation coefficients (r 2) of 0.9547 and 0.9226, respectively. All top three candidates had high docking scores, favourable pharmacophores and functional groups forming stable hydrogen bonds with HER2. These properties suggested stable binding affinities and favourable interaction with HER2. We concluded that these candidates may be further investigated as potential HER2 inhibitors. 相似文献
20.