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ABSTRACT: Our focus of current research is directed toward clarification of novel inhibitors (pyrazolo[1,5-a] pyrimidine (PP), thienopyridines (TP) and 2-ureido thiophene carboxamide (UTC) derivatives) targeting Checkpoint kinase 1 (CHK(1)), which is an oncology target of significant current interest. Our computational approaches include: (i) QSAR analysis was carried out on the computed steric/electrostatic/hydrophobic/hydrogen bond donor/hydrogen bond acceptor interactions with the pseudoreceptor surface, which yielded predictive models capable of explaining much of the variance of inhibitors. The resultant optimum QSAR/CoMFA models exhibited (N(training) = 51, N(test) = 16, R(cv) (2) = 0.47, R(pred) (2) = 0.7) for PP, (N(training) = 45, N(test) = 9, R(cv) (2) = 0.52, R(pred) (2) = 0.75) for TP and (N(training) = 58, N(test) = 15, R(cv) (2) = 0.67, R(pred) (2) = 0.88) for UTC. (ii) Molecular docking and molecular dynamics simulations experiments of the inhibitors into the binding site of CHK(1) aided the interpretation of the QSAR models and demonstrated the binding modes in the aspects of inhibitor's conformation, subsite interaction, and hydrogen bonding interactions, which indicated that a set of critical residues (Cys87, Glu91, Glu85, Ser147, Asp148, Glu17, Leu84 and Asn135) played a key role in the drug-target interactions. The obtained results in the present work will be fruitful for the design of new potent and selective inhibitors of CHK(1).
Journal of Molecular Modeling 01/2012; 18(7):3227-42. · 1.80 Impact Factor
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ABSTRACT: The phosphatidylinositol 3-kinase α (PI3Kα) was genetically validated as a promising therapeutic target for developing novel anticancer drugs. In order to explore the structure-activity correlation of benzothiazole series as inhibitors of PI3Kα, comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) were performed on 61 promising molecules to build 3D-QSAR models based on both the ligand- and receptor-based methods. The best CoMFA and CoMSIA models had a cross-validated coefficient r(cv)(2) of 0.618 and 0.621, predicted correlation coefficient r(pred) (2) of 0.812 and 0.83, respectively, proving their high correlative and predictive abilities on both the training and test sets. In addition, docking analysis and molecular dynamics simulation (MD) were also applied to elucidate the probable binding modes of these inhibitors at the ATP binding pocket. Based on the contour maps and MD results, some key structural factors responsible for the activity of this series of compounds were revealed as follows: (1) Ring-A has a strong preference for bulky hydrophobic or aromatic groups; (2) Electron-withdrawing groups at the para position of ring-B and hydrophilic substituents in ring-B region may benefit the potency; (3) A polar substituent like -NHSO(2)- between ring-A and ring-B can enhance the activity of the drug by providing hydrogen bonding interaction with the protein target. The satisfactory results obtained from this work strongly suggest that the developed 3D-QSAR models and the obtained PI3Kα inhibitor binding structures are reasonable for the prediction of the activity of new inhibitors and be helpful in future PI3Kα inhibitor design.
Journal of Molecular Modeling 12/2011; 18(7):2943-58. · 1.80 Impact Factor
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ABSTRACT: Nicotinic acetylcholine receptor (nAChR) is a target for insect-selective neonicotinoid insecticides (NNs), exemplified by imidacloprid (IMI). In the present study, 78 IMI derivatives reported as inhibitors of Drosophila melanogaster nAChR (Dm-nAChR) and Musca domestica nAChR (Md-nAChR) were used for three-dimensional quantitative structure-activity relationship (3D-QSAR) studies. Two optimal models with good predictive power were obtained: Q(2) = 0.64, R(2)(pred) = 0.72 for Dm-nAChR, and Q(2) = 0.63, R(2)(pred) = 0.62 for Md-nAChR. In addition, homology modeling, molecular dynamic (MD) simulation, and molecular docking also showed that amino acids located within loops A, C, D and E play key roles in the interaction of Dm-/Md-nAChR with NNs. This is highly consistent with the results of graphical analysis of 3D-QSAR contour plots. Mutation analysis also implicates the Y/S mutation within loop B as being associated closely with NN resistance in Drosophila and Musca. The results obtained lead to a better understanding not only of interactions between these antagonists and Dm-/Md-nAChR, but also of the essential features that should be considered when designing novel inhibitors with desired activities.
Journal of Molecular Modeling 11/2011; 18(6):2279-89. · 1.80 Impact Factor
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ABSTRACT: CDK₂ (cyclin-dependent kinase 2) is an attractive target for therapeutic intervention in cancer. In this work, quantitative structure-activity relationship (QSAR), molecular docking, and molecular dynamics (MD) studies were performed on three sets of 155 CDK₂ inhibitors. The obtained models exhibit good predictive capability in both internal and external validations (q²=0.73, r²(pred)=0.94 for 6, 6-dimethyl pyrrolo [3,4-c]pyrazoles analogs, q²=0.62, r²(pred)=0.63 for imidazole pyrimidine amides analogs and q²=0.56, r²(pred)=0.58 for 4-(pyrazol-4-yl)-pyrimidines analogs). Furthermore, a comparison between 3D-contour map, docking and MD simulation explore in detail the binding modes and the key structural features impacting the interaction of each series of inhibitors with the CDK₂ enzyme, which should be useful to aid the designing of new inhibitors with CDK₂ improved biological response.
Journal of molecular graphics & modelling 06/2011; 30:67-81. · 2.17 Impact Factor
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ABSTRACT: 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 (HDM(2)) via ubiquitination. Therefore, the design of inhibitors of HDM(2) 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-HDM(2) 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 HDM(2) 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 R(1) and R(3) regions should have small electronegativity groups; substituents R(2) and R(4) should be larger, and R(3) 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-HDM(2) interactions and be helpful for facilitating the design of novel potent inhibitors.
Journal of Molecular Modeling 04/2011; 18(1):295-306. · 1.80 Impact Factor
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ABSTRACT: Aims: To determine the capacity of secondary metabolite of strain SX-4, to enhance the nonspecific immunity and survival of carp (Cyprinus carpio), and to identify the constituents that are responsible. Methods and Results: A thermophilic strain SX-4 that is able to produce immunostimulatory metabolite was isolated from sludge sample of hot spring and identified by comparison with 16S rRNA sequences (99% of homology) as Anoxybacillus flavithermus. Bioactivity-guided fractionation of methanol extract from its cell-free culture, one bacterial peptide with the capacity of improving the nonspecific immune responses and disease resistance (relative per cent survival = 66·67%) was obtained and the compound was characterized as cyclo-(L-Pro-Gly) by IR, ESI-MS, (1) H NMR and (13) C NMR spectroscopic analyses. After intraperitoneal administration of this peptide, selected innate immune parameters including phagocytic activity, superoxide anion production, serum lysozyme activity and serum SOD activity, along with immune-related genes expression (i.e. interleukin-1β and inducible nitric oxide synthase), in the blood were found to be significantly increased. Conclusions: The bacterial peptide cyclo-(L-Pro-Gly) significantly enhances nonspecific immunity and survival of carp. Significance and Impact of the Study: There is a possibility of using cyclo-(L-Pro-Gly) as a better natural immunostimulant, which could have a promising role in aquaculture to prevent diseases and disease outbreaks.
Journal of Applied Microbiology 02/2011; · 2.34 Impact Factor
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ABSTRACT: Hsp90 is involved in correcting, folding, maturation and activation of a diverse array of client proteins; it has also been implicated in the treatment of cancer in recent years. In this work, comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), molecular docking and molecular dynamics were performed on three different series of Hsp90 inhibitors to build 3D-QSAR models, which were based on the ligand-based or receptor-based methods. The optimum 3D-QSAR models exhibited reasonable statistical characteristics with averaging internal q(2) > 0.60 and external r(2) (pred) > 0.66 for Benzamide tetrahydro-4H-carbazol-4-one analogs (BT), AT13387 derivatives (AT) and Dihydroxylphenyl amides (DA). The results revealed that steric effects contributed the most to the BT model, whereas H-bonding was more important to AT, and electrostatic, hydrophobic, H-bond donor almost contributed equally to the DA model. The docking analysis showed that Asp93, Tyr139 and Thr184 in Hsp90 are important for the three series of inhibitors. Molecular dynamics simulation (MD) further indicated that the conformation derived from docking is basically consistent with the average structure extracted from MD simulation. These results not only lead to a better understanding of interactions between these inhibitors and Hsp90 receptor but also provide useful information for the design of new inhibitors with a specific activity.
International Journal of Molecular Sciences 01/2011; 12(2):946-70. · 2.60 Impact Factor
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ABSTRACT: An abnormal ubiquitin-proteasome is found in many human diseases, especially in cancer, and has received extensive attention as a promising therapeutic target in recent years. In this work, several in silico models have been built with two classes of proteasome inhibitors (PIs) by using 3D-QSAR, homology modeling, molecular docking and molecular dynamics (MD) simulations. The study resulted in two types of satisfactory 3D-QSAR models, i.e., the CoMFA model (Q(2) = 0.462, R(2) (pred) = 0.820) for epoxyketone inhibitors (EPK) and the CoMSIA model (Q(2) = 0.622, R(2) (pred) = 0.821) for tyropeptin-boronic acid derivatives (TBA). From the contour maps, some key structural factors responsible for the activity of these two series of PIs are revealed. For EPK inhibitors, the N-cap part should have higher electropositivity; a large substituent such as a benzene ring is favored at the C6-position. In terms of TBA inhibitors, hydrophobic substituents with a larger size anisole group are preferential at the C8-position; higher electropositive substituents like a naphthalene group at the C3-position can enhance the activity of the drug by providing hydrogen bond interaction with the protein target. Molecular docking disclosed that residues Thr60, Thr80, Gly106 and Ser189 play a pivotal role in maintaining the drug-target interactions, which are consistent with the contour maps. MD simulations further indicated that the binding modes of each conformation derived from docking is stable and in accord with the corresponding structure extracted from MD simulation overall. These results can offer useful theoretical references for designing more potent PIs.
International Journal of Molecular Sciences 01/2011; 12(3):1807-35. · 2.60 Impact Factor
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ABSTRACT: In order to obtain structural features of 3-arylpyrimidin-2,4-diones emerged as promising inhibitors of insect γ-aminobutyric acid (GABA) receptor, a set of ligand-/receptor-based 3D-QSAR models for 60 derivatives are generated using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA). The statistically optimal CoMSIA model is produced with highest q(2) of 0.62, r(2) (ncv) of 0.97, and r(2) (pred) of 0.95. A minor/bulky electronegative hydrophilic polar substituent at the 1-/6-postion of the uracil ring, and bulky substituents at the 3'-, 4'- and 5'-positions of the benzene ring are beneficial for the enhanced potency of the inhibitors as revealed by the obtained 3D-contour maps. Furthermore, homology modeling, molecular dynamics (MD) simulation and molecular docking are also carried out to gain a better understanding of the probable binding modes of these inhibitors, and the results show that residues Ala-183(C), Thr-187(B), Thr-187(D) and Thr-187(E) in the second transmembrane domains of GABA receptor are responsible for the H-bonding interactions with the inhibitor. The good correlation between docking observations and 3D-QSAR analyses further proves the model reasonability in probing the structural features and the binding mode of 3-arylpyrimidin-2,4-dione derivatives within the housefly GABA receptor.
International Journal of Molecular Sciences 01/2011; 12(9):6293-311. · 2.60 Impact Factor
