3D-QSAR research of curcumin derivatives

Curcumin exhibits a great ability in various biological and pharmacological activities. Evaluation of curcumin derivatives served to establish the three-dimensional quantitative structure–activity relationship (3D-QSAR) model which was validated by the evaluation of a serial of 22 compounds. Two favorable 3D-QSAR models (CoMFA with q ² = 0.539, R ² = 0.981; CoMSIA with q ² = 0.451, R ² = 0.907) had been developed to predict the biological activity of curcumin derivatives, and external metric q _pred ² (CoMFA with 0.79; CoMSIA with 0.78) and r _m ² _(overall) (CoMFA with 0.71; CoMSIA with 0.56) were applied to evaluate the ability of prediction. Comparing the results obtained from both standard models, we found that reducing the carbon chains of curcumin (S2 and A1 zones) could increase its MCF-7 cytotoxicity; exchanging acceptor/donor substituent on A2 and A4, A3 and D3 zones could turnover its cytotoxicity of MCF-7. These results help with understanding the specific activity of curcumin compounds and designing new specific MCF-7 inhibitors.     

Structural characterization of human CRTh2: a combined homology modeling,molecular docking and 3D-QSAR-based in silico approach

Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) is an important therapeutic target for the treatment of asthma, chronic obstructive pulmonary disease, allergic rhinitis and atopic dermatitis. In this study, we report the binding site analysis of CRTh2 through molecular docking and quantitative structure–activity relationship (QSAR) studies to explore the interaction of 2-(2-(benzylthio)-1H-benzo[d]imidazol-1-yl) acetic acid derivatives. Various comparative models were generated using the available crystal structure of human delta opioid receptor (4N6H) as the template, and benzylthio acetic acid derivatives were docked into the predicted binding site region of human CRTh2 receptor. Surflex docking studies enabled us to identify that K5.43, Y4.60, N185, Y6.51, Q5.36, E6.58, T7.38 and H6.52 residues were the most crucial amino acids interacting with the ligand. In addition to docking, atom-by-atom matching and structure-based 3D-QSAR method CoMFA was performed. Based on better q ² and r ² _pred values, the best predictions were obtained for the ligand-based (q ² = 0.552, r ² _pred = 0.636) and for receptor-based (q ² = 0.507, r ² _pred = 0.541) QSAR model, whose robustness and predictability were verified by external test set validation. The results correlate well with the previously reported mouse model, and our study serves as a guide for mutational studies of human CRTh2 and further experimental investigations on the synthesis of new CRTh2 antagonist.     

Design and prediction of new acetylcholinesterase inhibitor via quantitative structure activity relationship of huprines derivatives

Acetylcholinesterase (AChE) is an important enzyme in the pathogenesis of Alzheimer’s disease (AD). Comparative quantitative structure-activity relationship (QSAR) analyses on some huprines inhibitors against AChE were carried out using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and hologram QSAR (HQSAR) methods. Three highly predictive QSAR models were constructed successfully based on the training set. The CoMFA, CoMSIA, and HQSAR models have values of r ² = 0.988, q ² = 0.757, ONC = 6; r ² = 0.966, q ² = 0.645, ONC = 5; and r ² = 0.957, q ² = 0.736, ONC = 6. The predictabilities were validated using an external test sets, and the predictive r ² values obtained by the three models were 0.984, 0.973, and 0.783, respectively. The analysis was performed by combining the CoMFA and CoMSIA field distributions with the active sites of the AChE to further understand the vital interactions between huprines and the protease. On the basis of the QSAR study, 14 new potent molecules have been designed and six of them are predicted to be more active than the best active compound 24 described in the literature. The final QSAR models could be helpful in design and development of novel active AChE inhibitors.     

QSAR and docking studies of novel β-carboline derivatives as anticancer

Quantitative structure–activity relationship (QSAR) studies were performed on β-carboline derivatives for prediction of anticancer activity. The statistically significant 2D-QSAR model having r ² = 0.726 and q ² = 0.654 with pred_r ² = 0.763 was developed by stepwise multiple linear regression method. In order to understand the structural requirement of these β-carboline derivatives, a ligand-based pharmacophore 3D-QSAR model was developed. The five-point pharmacophore hypothesis yielded a 3D-QSAR model with good partial least-square statistics results (r ² = 0.73, Q _ext ²  = 0.755, F = 67.5, SD = 0.245, RMSE = 0.241, Pearson-R = 0.883). A docking study revealed the binding orientations of these derivatives at the active site amino residues of DNA intercalate (PDB ID: 1D12). The results of 2D-QSAR, atom-based 3D-QSAR, and docking studies gave detailed structural insights as well as highlighted important binding features of β-carboline derivatives as anticancer agent which provided guidance for the rational design of novel potent anticancer agents.     

Molecular modeling studies on series of Btk inhibitors using docking,structure-based 3D-QSAR and molecular dynamics simulation: a combined approach

Bruton tyrosine kinase (Btk) is a non-receptor tyrosine kinase. It is a crucial component in BCR pathway and expressed only in hematopoietic cells except T cells and Natural killer cells. BTK is a promising target because of its involvement in signaling pathways and B cell diseases such as autoimmune disorders and lymphoma. In this work, a combined molecular modeling study of molecular docking, 3D-QSAR and molecular dynamic (MD) simulation were performed on a series of 2,5-diaminopyrimidine compounds as inhibitors targeting Btk kinase to understand the interaction and key residues involved in the inhibition. A structure based CoMFA (q ² = 0.675, NOC = 5, r ² = 0.961) and COMSIA (q ² = 0.704, NOC = 6, r ² = 0.962) models were developed from the conformation obtained by docking. The developed models were subjected to various validation techniques such as leave-five-out, external test set, bootstrapping, progressive sampling and rm ² metrics and found to have a good predictive ability in both internal and external validation. Our docking results showed the important residues that interacts in the active site residues in inhibition of Btk kinase. Furthermore, molecular dynamics simulation was employed to study the stability of the docked conformation and to investigate the binding interactions in detail. The MD simulation analyses identified several important hydrogen bonds with Btk, including the gatekeeper residue Thr474 and Met477 at the hinge region. Hydrogen bond with active site residues Leu408 and Arg525 were also recognized. A good correlation between the MD results, docking studies and the contour map analysis are observed. This indicates that the developed models are reliable. Our results from this study can provide insights in the designing and development of more potent Btk kinase inhibitors.     

3D-QSAR of amino-substituted pyrido[3,2B]pyrazinones as PDE-5 inhibitors

A 3D-QSAR study on amino-substituted pyrido[3,2b]pyrazinones as PDE-5 inhibitors was successfully performed by means of pharmacophore mapping using PHASE module of Schrödinger-9. The 3D-QSAR obtained from AADHRR-183 hypothesis was found to be statistically good with r ² = 0.95 and q ² = 0.81 taking PLS factor 4. The statistical significance of the model was also confirmed by a high value of Fisher ratio of 85.1 and a very low value of RMSE 0.29. One of the other parameters which signify the model predictivity is Pearson R. Its value of 0.91 shows that the correlation between predicted and observed activities for the test set compounds is excellent. Hydrophobic groups are important for PDE-5 inhibition while H-bond donor groups are less favorable for the same. Electron withdrawing groups are favorable if include at ring A in the structures while unfavorable at other sites. Thus, it can be assumed that the present QSAR analysis is enough to demonstrate PDE-5 inhibition with the help of AADHRR-183 hypothesis and will help in designing novel and potent PDE-5 inhibitors.     

Molecular modeling studies of 3-acyl-2-phenylamino-1,4-dihydroquinolin-4-one derivatives as phosphatase SerB653 inhibitors

To understand the quantitative structure–activity relationships properties of 3-acyl-2-phenylamino-1,4-dihydroquinolin-4-one derivatives, and to design inhibitors of phosphatase SerB653 were developed. The statistical parameters of two-dimensional quantitative structure–activity relationship model showed it has good reliability and predictive ability (q ²?=?0.7180, F test?=?62.046, pred_r ²?=?0.7519). The best two-dimensional model suggests a chlorine atom substitution at position X⁴ and Y¹ for enhance activity. Three-dimensional quantitative structure–activity relationship was carried out using k-nearest neighbor method and showed cross-validated correlation coefficient (q ²) of 0.7484, and a predicted r ² for the external test (pred_r ²) of 0.6895 were obtained with best three-dimensional quantitative structure–activity relationship model. The influences of steric and electrostatic field effects generated by the contribution plot are analyzed. Pharmacophore approach for SerB653 inhibitor consists of hydrogen bond acceptor, hydrogen bond donor, and aromatic region. Two-dimensional quantitative structure–activity relationship and three-dimensional quantitative structure–activity relationship, pharmacophore analyses of 3-acyl-2-phenylamino-1,4-dihydroquinolin-4-one derivatives can provide more useful information and important structural insights for designing potent phosphatase SerB653 inhibitors.     

Identification of structural requirements of estrogen receptor modulators using pharmacoinformatics techniques for application to estrogen therapy

In this study, we explored the structural requirements of known estrogen receptor modulators for biological activity using pharmacoinformatics approaches to elucidate critical functionalities for new, potent and less toxic chemical agents for successful application in estrogen therapy. For this purpose, a group of nonsteroidal ligands 7-thiabicyclo[2.2.1]hept-2-ene-7-oxide derivatives were collected from the literature to perform quantitative structure–activity relationship (QSAR), pharmacophore and molecular docking studies. The 2D QSAR models (R _α ²  = 0.857, se _α  = 0.370, Q _α ²  = 0.848, R _pred?α ²  = 0.675, s _pα  = 0.537; R _β ²  = 0.874, se _β  = 0.261, Q _β ²  = 0.859, R _pred?β ²  = 0.659, s _pβ  = 0.408) explained that hydrophobicity and molar refractivity were crucial for binding affinity in both α- and β-subtypes. The space modeling study (R _α ²  = 0.955, se _α  = 1.311, Q _α ²  = 0.932, R _pred?α ²  = 0.737, s _pα  = 0.497; R _β ²  = 0.885, se _β  = 1.328, Q _β ²  = 0.878, R _pred?β ²  = 0.769, s _pβ  = 0.336) revealed the importance of HB donor and hydrophobic features for both subtypes, whereas HB acceptor and aromatic ring were critical for α- and β-subtypes, respectively. The functionalities developed in the QSAR and pharmacophore studies were substantiated by molecular docking studies which provided the preferred orientation of ligands for effective interaction at the active site cavity.     

Molecular docking and 3D-QSAR studies on checkpoint kinase 1 inhibitors

Checkpoint kinase 1(Chk1) is a promising target for cancer treatment. Here three-dimensional quantitative structure–activity relationship (3D-QSAR) studies were performed on 174 1,4-dihydroindeno[1,2-c]pyrazole inhibitors of Chk1 using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Two satisfactory ligand-based QSAR models were built (CoMFA model: q ² = 0.541, r ² = 0.880, CoMSIA model: q ² = 0.590, r ² = 0.902). The docking-based studies presented a detailed understanding of interaction between the inhibitors and Chk1. The obtained QSAR models are highly predictable (CoMFA model: q ² = 0.567, r ² = 0.891, CoMSIA model: q ² = 0.596, r ² = 0.917). The models were further validated by an external testing set obtaining $ r_{\text{pred}}^{2} $ r pred 2 values 0.896 and 0.923 for CoMFA and CoMSIA, respectively. So our models might be helpful for further modification of 1,4-dihydroindeno[1,2-c]pyrazole derivatives.     

Effect of Cd<Superscript>+2</Superscript> on phosphate solubilizing abilities and hydrogen peroxide production of soil-borne micromycetes isolated from <Emphasis Type="Italic">Phragmites australis</Emphasis>-rhizosphere

The aims of this work were to evaluate the phosphate-solubilization and hydrogen peroxide (H₂O₂) production by the soil-borne micromycetes, Aspergillus japonicus, Penicillium italicum and Penicillium dipodomyicola, isolated from Phragmites australis rhizosphere and to study the effect of several concentrations of Cadmium (Cd²⁺) on both variables. Our results showed that P. italicum achieved a higher P-solubilization and H₂O₂ production than A. japonicus and P. dipodomyicola, as only P. italicum showed a positive correlation (R² = 0.71) between P-solubilization and H₂O₂ production. In dose–response assays, P. italicum was also more tolerant to Cd²⁺ (0.31 mM) in comparison to A. japonicus (0.26 mM). Analysis of the 2⁴ factorial experimental design showed that P-solubilization by P. italicum was negatively affected by increases in Cd²⁺ (p = 0.04) and yeast extract (p = 0.02) in the culture medium. The production of H₂O₂ was positively affected only by glucose (p = 0.002). Fungal biomass production was reduced significantly (p = 0.0009) by Cd²⁺ and increased (p = 0.0003) by high glucose concentration in the culture medium. The tolerance and correlation between P-solubilization and H₂O₂ production in the presence of Cd²⁺ was strain and species dependent. The effects of Cd²⁺, glucose, ammonium sulfate and yeast extract on those variables were evaluated through a two-level factorial design. P. italicum is promising for P-solubilization in soils contaminated with Cd²⁺ and may be an alternative for manufacture of biofertilizers to replace chemical fertilizers.     

A comprehensive structure–activity analysis 2,3,5-trisubstituted 4,5-dihydro-4-oxo-3H-imidazo [4,5-c] pyridine derivatives as angiotensin II receptor antagonists: using 2D- and 3D-QSAR approach

The QSAR studies were performed on a series of 2,3,5-trisubstituted 4,5-dihydro-4-oxo-3H-imidazo [4,5-c] pyridine derivatives as angiotensin II AT₁ receptor antagonists activity to find out the structural features requirements for the antihypertensive activity. The QSAR study was carried out on V-life Molecular Design Suite software and the derived best QSAR model by partial least square principal component regression and multiple linear regression method showed variation in biological activity. The statistically best significant model with high-correlation coefficient (r ² = 0.9425) was selected for further study and the resulted validation parameters of the model, cross-validated correlation coefficient (q ² = 0.7786 and pred_r ² = 0.8562) show the model has good predictive activities. The model showed that the parameters SdssCcount, SssNHcount, and SaaaCcount and H_Donor count are highly correlated with angiotensin II AT₁ receptor antagonists activity of 2,3,5-trisubstituted 4,5-dihydro-4-oxo-3H-imidazo [4,5-c] pyridine derivatives. Partial least square (PLS) methodology coupled with various feature selection methods viz. stepwise, simulated annealing and genetic algorithm were applied to derive 3D-QSAR models which were further validated for statistical significance and predictive ability by internal and external validation. Molecular field analysis was used to construct the best 3D-QSAR model-7 using k-nearest neighbor (kNN) method, showing good correlative and predictive capabilities in terms of q ² = 0.8316 and pred_r ² = 0.8152. Both 2D-and 3D-QSAR study of such derivatives provide guidance for further lead optimization and designing of potent anti-hypertensive agents.     

Pharmacophore modeling and 3D-QSAR studies of galloyl benzamides as potent P-gp inhibitors

P-gp transporter regulates key ADME of drugs in MDR condition. In the present work, a pharmacophore-based 3D-QSAR model was generated for a series of galloyl benzamides analogs possessing P-gp inhibitory activity. Developed pharmacophore model contains two hydrogen-bond acceptors (A), one hydrophobic (H), one hydrogen-bond donor (D) and two aromatic rings (R). These are crucial molecular fingerprints which predict binding efficacy of high-affinity and low-affinity ligands to the P-gp efflux pump. These pharmacophoric features point toward key structural requirements of galloyl benzamides for potent P-gp inhibition. Furthermore, a biological correlation 3D-QSAR variants and functional fingerprints of P-gp responsible for the receptor binding were observed. Alignment of the developed model with P-gp crystal structure indicated importance of A2 and A4 H-bond acceptor sites, which are involved in the important interactions with Glu530 and His690 residues of the active site. Excellent statistical results of QSAR model such as good correlation coefficient (r ² > 0.95), higher F value (F > 205) and excellent predictive power (Q ² > 0.6) with low standard deviation (SD < 0.2) strongly suggest that the developed model is good for the future prediction of P-gp inhibitory activity of new galloyl benzamide analogs.     

Levetiracetam versus phenytoin for seizure prophylaxis in brain injured patients: a systematic review and meta-analysis

Background The onset of early and/or late seizures in brain injured patients is associated with worse outcome. So far, phenytoin is the most commonly used antiepileptic drug to prevent seizures in this group of patients. Objective In the current metaanalysis, we aimed to compare the efficacy and safety of phenytoin versus levetiracetam for seizure prophylaxis in brain injured patients. Methods A systematic search was conducted in PubMed and Cochrane Library Database by 2 investigators. Four randomized controlled trials (RCTs) were included (295 patients). Data were extracted and the quality of each RCT was assessed. Results Levetiracetam was found to be more effective than phenytoin in seizure prophylaxis (OR = 0.23; CI 95% [0.09–0.56]; Q test p value = 0.18 and I² = 38%). A trend toward less serious side effects was also found in patients treated with levetiracetam (OR = 0.27; CI 95% [0.07–1.07]; Q test p value = 0.72 and I² = 0%). Conclusion Levetiracetam is more effective and safer than phenytoin for seizure prophylaxis in brain injured patients.     

Chemical composition and bioactivities of the essential oil from different organs of <Emphasis Type="Italic">Ferula communis</Emphasis> L. growing in Tunisia

The essential oils obtained by the hydrodistillation from the fresh flowers, leaves, stems, and roots of Ferula communis L., growing in Tunisia were analyzed by GC and GC/MS. Thirty-two components were identified in the oil of flowers with camphor (18.3 %), α-pinene (15.3 %), and β-eudesmol (9.3 %) as the main constituents. Twenty-nine compounds were identified in the oil of stems with β-eudesmol (28.1 %), δ-eudesmol (11.1 %), and α-eudesmol (9.6 %) as the main compounds. Twenty compounds were characterized in the oil of roots with dillapiole (7.9 %), guaiol (7.3 %), and spathulenol (6.8 %). In the oil of leaves, α-eudesmol (25.2 %), β-eudesmol (20.7 %), δ-eudesmol (10.1 %), and caryophyllene oxide (7.2 %) were found as the main constituents. This study was undertaken to evaluate the antioxidant activity using DPPH (2,2′-diphenyl-1-picrylhydrazyl), ABTS (2,2′-azinobis-3-ethylbenzothiazoline-6-sulfonic acid), reducing power, and catalase activity. We tested also the antibacterial, cytotoxic, and cholinesterase inhibition properties of the essential oil of different organs of F. communis. The essential oil of the stems showed the highest antioxidant activity (IC₅₀ = 0.03 ± 0.001 mg mL^?1), in DPPH assay and the important result of catalase (303.03 µmol H₂O₂ degraded/min/protein) of F. communis. The antibacterial activity of the oil was determined by micro-well dilution assay. The best results (MIC = 0.156 ± 0.02 mg mL^?1) were exhibited by the essential oil of the leaves of F. Communis against Pseudomonas aeruginosa. Besides, the strongest cytotoxic activity against Hela cells was shown with essential oils’ leaves with an inhibition percentage of 79.05 % at the concentration of 500 µg mL^?1. However, the best inhibition percentage of A 549 cells was detected for essential oils’ leaves with an inhibition percentage of 54.56 % at 250 µg mL^?1. Our finding showed that the essential oil of the flowers was the most active, with 64.623 % of inhibition against butyrylcholinesterase at 10 mg mL^?1 from the incubation time of 30 min.