International Journal of Molecular Sciences

Editorial

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Open AccessEditorial

Molecular Science for Drug Development and Biomedicine

by Wei-Zhu Zhong and Shu-Feng Zhou

Int. J. Mol. Sci. 2014, 15(11), 20072-20078; https://doi.org/10.3390/ijms151120072 - 4 Nov 2014

Cited by 83 | Viewed by 7731

Abstract

With the avalanche of biological sequences generated in the postgenomic age, molecular science is facing an unprecedented challenge, i.e., how to timely utilize the huge amount of data to benefit human beings. Stimulated by such a challenge, a rapid development has taken [...] Read more.

With the avalanche of biological sequences generated in the postgenomic age, molecular science is facing an unprecedented challenge, i.e., how to timely utilize the huge amount of data to benefit human beings. Stimulated by such a challenge, a rapid development has taken place in molecular science, particularly in the areas associated with drug development and biomedicine, both experimental and theoretical. The current thematic issue was launched with the focus on the topic of “Molecular Science for Drug Development and Biomedicine”, in hopes to further stimulate more useful techniques and findings from various approaches of molecular science for drug development and biomedicine.[...] Full article

(This article belongs to the Special Issue Molecular Science for Drug Development and Biomedicine)

Research

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1126 KiB

Open AccessArticle

Prediction of Multi-Target Networks of Neuroprotective Compounds with Entropy Indices and Synthesis, Assay, and Theoretical Study of New Asymmetric 1,2-Rasagiline Carbamates

by Francisco J. Romero Durán, Nerea Alonso, Olga Caamaño, Xerardo García-Mera, Matilde Yañez, Francisco J. Prado-Prado and Humberto González-Díaz

Int. J. Mol. Sci. 2014, 15(9), 17035-17064; https://doi.org/10.3390/ijms150917035 - 24 Sep 2014

Cited by 33 | Viewed by 7684

Abstract

In a multi-target complex network, the links (L_ij) represent the interactions between the drug (d_i) and the target (t_j), characterized by different experimental measures (K_i, K_m, IC₅₀, [...] Read more.

In a multi-target complex network, the links (L_ij) represent the interactions between the drug (d_i) and the target (t_j), characterized by different experimental measures (K_i, K_m, IC₅₀, etc.) obtained in pharmacological assays under diverse boundary conditions (c_j). In this work, we handle Shannon entropy measures for developing a model encompassing a multi-target network of neuroprotective/neurotoxic compounds reported in the CHEMBL database. The model predicts correctly >8300 experimental outcomes with Accuracy, Specificity, and Sensitivity above 80%–90% on training and external validation series. Indeed, the model can calculate different outcomes for >30 experimental measures in >400 different experimental protocolsin relation with >150 molecular and cellular targets on 11 different organisms (including human). Hereafter, we reported by the first time the synthesis, characterization, and experimental assays of a new series of chiral 1,2-rasagiline carbamate derivatives not reported in previous works. The experimental tests included: (1) assay in absence of neurotoxic agents; (2) in the presence of glutamate; and (3) in the presence of H₂O₂. Lastly, we used the new Assessing Links with Moving Averages (ALMA)-entropy model to predict possible outcomes for the new compounds in a high number of pharmacological tests not carried out experimentally. Full article

(This article belongs to the Special Issue Molecular Science for Drug Development and Biomedicine)

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Open AccessArticle

Effects of the Novel Compound DK223 ([1E,2E-1,2-Bis(6-methoxy-2H-chromen-3-yl)methylene]hydrazine) on Migration and Proliferation of Human Keratinocytes and Primary Dermal Fibroblasts

by Manh Tin Ho, Hyun Sik Kang, Jung Sik Huh, Young Mee Kim, Yoongho Lim and Moonjae Cho

Int. J. Mol. Sci. 2014, 15(7), 13091-13110; https://doi.org/10.3390/ijms150713091 - 23 Jul 2014

Cited by 10 | Viewed by 7601

Abstract

Wound healing plays an important role in protecting the human body from external infection. Cell migration and proliferation of keratinocytes and dermal fibroblasts are essential for proper wound healing. Recently, several studies have demonstrated that secondary compounds produced in plants could affect skin [...] Read more.

Wound healing plays an important role in protecting the human body from external infection. Cell migration and proliferation of keratinocytes and dermal fibroblasts are essential for proper wound healing. Recently, several studies have demonstrated that secondary compounds produced in plants could affect skin cells migration and proliferation. In this study, we identified a novel compound DK223 ([1E,2E-1,2-bis(6-methoxy-2H-chromen-3-yl)methylene]hydrazine) that concomitantly induced human keratinocyte migration and dermal fibroblast proliferation. We evaluated the regulation of epithelial and mesenchymal protein markers, such as E-cadherin and Vimentin, in human keratinocytes, as well as extracellular matrix (ECM) secretion and metalloproteinase families in dermal fibroblasts. DK223 upregulated keratinocyte migration and significantly increased the epithelial marker E-cadherin in a time-dependent manner. We also found that reactive oxygen species (ROS) increased significantly in keratinocytes after 2 h of DK223 exposure, returning to normal levels after 24 h, which indicated that DK223 had an early shock effect on ROS production. DK223 also stimulated fibroblast proliferation, and induced significant secretion of ECM proteins, such as collagen I, III, and fibronectin. In dermal fibroblasts, DK223 treatment induced TGF-β1, which is involved in a signaling pathway that mediates proliferation. In conclusion, DK223 simultaneously induced both keratinocyte migration via ROS production and fibroblast proliferation via TGF-β1 induction. Full article

(This article belongs to the Special Issue Molecular Science for Drug Development and Biomedicine)

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Open AccessArticle

4-Hydroxyphenylacetic Acid Attenuated Inflammation and Edema via Suppressing HIF-1α in Seawater Aspiration-Induced Lung Injury in Rats

by Zhongyang Liu, Ronggang Xi, Zhiran Zhang, Wangping Li, Yan Liu, Faguang Jin and Xiaobo Wang

Int. J. Mol. Sci. 2014, 15(7), 12861-12884; https://doi.org/10.3390/ijms150712861 - 21 Jul 2014

Cited by 62 | Viewed by 7491

Abstract

4-Hydroxyphenylacetic acid (4-HPA) is an active component of Chinese herb Aster tataricus which had been widely used in China for the treatment of pulmonary diseases. The aim of this study is to investigate the effect of 4-HPA on seawater aspiration-induced lung injury. Pulmonary [...] Read more.

4-Hydroxyphenylacetic acid (4-HPA) is an active component of Chinese herb Aster tataricus which had been widely used in China for the treatment of pulmonary diseases. The aim of this study is to investigate the effect of 4-HPA on seawater aspiration-induced lung injury. Pulmonary inflammation and edema were assessed by enzyme-linked immunosorbent assay (ELISA), bronchoalveolar lavage fluid (BALF) white cell count, Evans blue dye analysis, wet to dry weight ratios, and histology study. Hypoxia-inducible factor-1α (HIF-1α) siRNA and permeability assay were used to study the effect of 4-HPA on the production of inflammatory cytokines and monolayer permeability in vitro. The results showed that 4-HPA reduced seawater instillation-induced mortality in rats. In lung tissues, 4-HPA attenuated hypoxia, inflammation, vascular leak, and edema, and decreased HIF-1α protein level. In primary rat alveolar epithelial cells (AEC), 4-HPA decreased hypertonicity- and hypoxia-induced HIF-1α protein levels through inhibiting the activations of protein translational regulators and via promoting HIF-1α protein degradation. In addition, 4-HPA lowered inflammatory cytokines levels through suppressing hypertonicity- and hypoxia-induced HIF-1α in NR8383 macrophages. Moreover, 4-HPA decreased monolayer permeability through suppressing hypertonicity and hypoxia-induced HIF-1α, which was mediated by inhibiting vascular endothelial growth factor (VEGF) in rat lung microvascular endothelial cell line (RLMVEC). In conclusion, 4-HPA attenuated inflammation and edema through suppressing hypertonic and hypoxic induction of HIF-1α in seawater aspiration-induced lung injury in rats. Full article

(This article belongs to the Special Issue Molecular Science for Drug Development and Biomedicine)

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Open AccessArticle

DADS Suppresses Human Esophageal Xenograft Tumors through RAF/MEK/ERK and Mitochondria-Dependent Pathways

by Xiaoran Yin, Jun Zhang, Xiaoning Li, Dong Liu, Cheng Feng, Rongrui Liang, Kun Zhuang, Chenlei Cai, Xinghuan Xue, Fuchun Jing, Xijing Wang, Jun Wang, Xinlian Liu and Hongbing Ma

Int. J. Mol. Sci. 2014, 15(7), 12422-12441; https://doi.org/10.3390/ijms150712422 - 14 Jul 2014

Cited by 36 | Viewed by 9002

Abstract

Diallyl disulfide (DADS) is a natural organosulfur compound isolated from garlic. DADS has various biological properties, including anticancer, antiangiogenic, and antioxidant effects. However, the anticancer mechanisms of DADS in human esophageal carcinoma have not been elucidated, especially in vivo. In this study, [...] Read more.

Diallyl disulfide (DADS) is a natural organosulfur compound isolated from garlic. DADS has various biological properties, including anticancer, antiangiogenic, and antioxidant effects. However, the anticancer mechanisms of DADS in human esophageal carcinoma have not been elucidated, especially in vivo. In this study, MTT assay showed that DADS significantly reduced cell viability in human esophageal carcinoma ECA109 cells, but was relatively less toxic in normal liver cells. The pro–apoptotic effect of DADS on ECA109 cells was detected by Annexin V-FITC/propidium iodide (PI) staining. Flow cytometry analysis showed that DADS promoted apoptosis in a dose-dependent manner and the apoptosis rate could be decreased by caspase-3 inhibitor Ac-DEVD-CHO. Xenograft study in nude mice showed that DADS treatment inhibited the growth of ECA109 tumor in both 20 and 40 mg/kg DADS groups without obvious side effects. DADS inhibited ECA109 tumor proliferation by down-regulating proliferation cell nuclear antigen (PCNA). DADS induced apoptosis by activating a mitochondria-dependent pathway with the executor of caspase-3, increasing p53 level and Bax/Bcl-2 ratio, and downregulating the RAF/MEK/ERK pathway in ECA109 xenograft tumosr. Based on studies in cell culture and animal models, the findings here indicate that DADS is an effective and safe anti-cancer agent for esophageal carcinoma. Full article

(This article belongs to the Special Issue Molecular Science for Drug Development and Biomedicine)

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Open AccessArticle

Elucidating Polypharmacological Mechanisms of Polyphenols by Gene Module Profile Analysis

by Bin Li, Min Xiong and Hong-Yu Zhang

Int. J. Mol. Sci. 2014, 15(7), 11245-11254; https://doi.org/10.3390/ijms150711245 - 25 Jun 2014

Cited by 13 | Viewed by 6065

Abstract

Due to the diverse medicinal effects, polyphenols are among the most intensively studied natural products. However, it is a great challenge to elucidate the polypharmacological mechanisms of polyphenols. To address this challenge, we establish a method for identifying multiple targets of chemical agents [...] Read more.

Due to the diverse medicinal effects, polyphenols are among the most intensively studied natural products. However, it is a great challenge to elucidate the polypharmacological mechanisms of polyphenols. To address this challenge, we establish a method for identifying multiple targets of chemical agents through analyzing the module profiles of gene expression upon chemical treatments. By using FABIA algorithm, we have performed a biclustering analysis of gene expression profiles derived from Connectivity Map (cMap), and clustered the profiles into 49 gene modules. This allowed us to define a 49 dimensional binary vector to characterize the gene module profiles, by which we can compare the expression profiles for each pair of chemical agents with Tanimoto coefficient. For the agent pairs with similar gene expression profiles, we can predict the target of one agent from the other. Drug target enrichment analysis indicated that this method is efficient to predict the multiple targets of chemical agents. By using this method, we identify 148 targets for 20 polyphenols derived from cMap. A large part of the targets are validated by experimental observations. The results show that the medicinal effects of polyphenols are far beyond their well-known antioxidant activities. This method is also applicable to dissect the polypharmacology of other natural products. Full article

(This article belongs to the Special Issue Molecular Science for Drug Development and Biomedicine)

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PSNO: Predicting Cysteine S-Nitrosylation Sites by Incorporating Various Sequence-Derived Features into the General Form of Chou’s PseAAC

by Jian Zhang, Xiaowei Zhao, Pingping Sun and Zhiqiang Ma

Int. J. Mol. Sci. 2014, 15(7), 11204-11219; https://doi.org/10.3390/ijms150711204 - 25 Jun 2014

Cited by 92 | Viewed by 7775

Abstract

S-nitrosylation (SNO) is one of the most universal reversible post-translational modifications involved in many biological processes. Malfunction or dysregulation of SNO leads to a series of severe diseases, such as developmental abnormalities and various diseases. Therefore, the identification of SNO sites (SNOs) [...] Read more.

S-nitrosylation (SNO) is one of the most universal reversible post-translational modifications involved in many biological processes. Malfunction or dysregulation of SNO leads to a series of severe diseases, such as developmental abnormalities and various diseases. Therefore, the identification of SNO sites (SNOs) provides insights into disease progression and drug development. In this paper, a new bioinformatics tool, named PSNO, is proposed to identify SNOs from protein sequences. Firstly, we explore various promising sequence-derived discriminative features, including the evolutionary profile, the predicted secondary structure and the physicochemical properties. Secondly, rather than simply combining the features, which may bring about information redundancy and unwanted noise, we use the relative entropy selection and incremental feature selection approach to select the optimal feature subsets. Thirdly, we train our model by the technique of the k-nearest neighbor algorithm. Using both informative features and an elaborate feature selection scheme, our method, PSNO, achieves good prediction performance with a mean Mathews correlation coefficient (MCC) value of about 0.5119 on the training dataset using 10-fold cross-validation. These results indicate that PSNO can be used as a competitive predictor among the state-of-the-art SNOs prediction tools. A web-server, named PSNO, which implements the proposed method, is freely available at http://59.73.198.144:8088/PSNO/. Full article

(This article belongs to the Special Issue Molecular Science for Drug Development and Biomedicine)

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Synthesis and Antioxidant Activity Evaluation of New Compounds from Hydrazinecarbothioamide and 1,2,4-Triazole Class Containing Diarylsulfone and 2,4-Difluorophenyl Moieties

by Stefania-Felicia Barbuceanu, Diana Carolina Ilies, Gabriel Saramet, Valentina Uivarosi, Constantin Draghici and Valeria Radulescu

Int. J. Mol. Sci. 2014, 15(6), 10908-10925; https://doi.org/10.3390/ijms150610908 - 17 Jun 2014

Cited by 85 | Viewed by 8711

Abstract

In the present investigation, new hydrazinecarbothioamides 4–6 were synthesized by reaction of 4-(4-X-phenylsulfonyl)benzoic acids hydrazides (X= H, Cl, Br) 1–3 with 2,4-difluorophenyl isothiocyanate and further these were treated with sodium hydroxide to obtain 1,2,4-triazole-3-thione derivatives 7–9. [...] Read more.

In the present investigation, new hydrazinecarbothioamides 4–6 were synthesized by reaction of 4-(4-X-phenylsulfonyl)benzoic acids hydrazides (X= H, Cl, Br) 1–3 with 2,4-difluorophenyl isothiocyanate and further these were treated with sodium hydroxide to obtain 1,2,4-triazole-3-thione derivatives 7–9. The reaction of 7–9 with α-halogenated ketones, in basic media, afforded new S-alkylated derivatives 10–15. The structures of the synthesized compounds have been established on the basis of ¹H-NMR, ¹³C-NMR, IR, mass spectral studies and elemental analysis. The antioxidant activity of all compounds has been screened. Hydrazinecarbothioamides 4–6 showed excellent antioxidant activity and 1,2,4-triazole-3-thiones 7–9 showed good antioxidant activity using the DPPH method. Full article

(This article belongs to the Special Issue Molecular Science for Drug Development and Biomedicine)

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Open AccessArticle

Qualitative Analysis of the Helical Electronic Energy of Inherently Chiral Calix[4]arenes: An Approach to Effectively Assign Their Absolute Configuration

by Shuang Zheng, Ming-Liang Chang, Jing Zhou, Jing-Wei Fu, Qing-Wei Zhang, Shao-Yong Li, Wei Qiao and Jun-Min Liu

Int. J. Mol. Sci. 2014, 15(6), 9844-9858; https://doi.org/10.3390/ijms15069844 - 3 Jun 2014

Cited by 1 | Viewed by 5574

Abstract

For all microhelices on aromatic rings of inherently chiral calix[4]arene, an expression was derived from one approximation and one hypothesis on the basis of the electron-on-a-helix model of Tinoco and Woody as follows: 1/E = μ (H − K Δα [...] Read more.

For all microhelices on aromatic rings of inherently chiral calix[4]arene, an expression was derived from one approximation and one hypothesis on the basis of the electron-on-a-helix model of Tinoco and Woody as follows: 1/E = μ (H − K Δα²) , where μ = 1 for the right-handed microhelix and μ = −1 for the left-handed microhelix; and H and K are constant and greater than zero. The expression correlates microhelical electronic energy (E) with the atom polarizability difference (Δα) on both microhelix ends, which intuitively and clearly shows the impact of helical substituent polarizability on helical electronic energy. The case analysis almost entirely proves that the qualitative analysis of the helical electronic energy of inherently chiral calix[4]arenes with the expression is scientific and can be used to effectively assign their absolute configuration Full article

(This article belongs to the Special Issue Molecular Science for Drug Development and Biomedicine)

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Open AccessCommunication

Synthesis, Preliminary Bioevaluation and Computational Analysis of Caffeic Acid Analogues

by Zhiqian Liu, Jianjun Fu, Lei Shan, Qingyan Sun and Weidong Zhang

Int. J. Mol. Sci. 2014, 15(5), 8808-8820; https://doi.org/10.3390/ijms15058808 - 16 May 2014

Cited by 8 | Viewed by 7195

Abstract

A series of caffeic acid amides were designed, synthesized and evaluated for anti-inflammatory activity. Most of them exhibited promising anti-inflammatory activity against nitric oxide (NO) generation in murine macrophage RAW264.7 cells. A 3D pharmacophore model was created based on the biological results for [...] Read more.

A series of caffeic acid amides were designed, synthesized and evaluated for anti-inflammatory activity. Most of them exhibited promising anti-inflammatory activity against nitric oxide (NO) generation in murine macrophage RAW264.7 cells. A 3D pharmacophore model was created based on the biological results for further structural optimization. Moreover, predication of the potential targets was also carried out by the PharmMapper server. These amide analogues represent a promising class of anti-inflammatory scaffold for further exploration and target identification. Full article

(This article belongs to the Special Issue Molecular Science for Drug Development and Biomedicine)

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The Discovery of Potentially Selective Human Neuronal Nitric Oxide Synthase (nNOS) Inhibitors: A Combination of Pharmacophore Modelling, CoMFA, Virtual Screening and Molecular Docking Studies

by Guanhong Xu, Yue Chen, Kun Shen, Xiuzhen Wang, Fei Li and Yan He

Int. J. Mol. Sci. 2014, 15(5), 8553-8569; https://doi.org/10.3390/ijms15058553 - 14 May 2014

Cited by 10 | Viewed by 7218

Abstract

Neuronal nitric oxide synthase (nNOS) plays an important role in neurotransmission and smooth muscle relaxation. Selective inhibition of nNOS over its other isozymes is highly desirable for the treatment of neurodegenerative diseases to avoid undesirable effects. In this study, we present a workflow [...] Read more.

Neuronal nitric oxide synthase (nNOS) plays an important role in neurotransmission and smooth muscle relaxation. Selective inhibition of nNOS over its other isozymes is highly desirable for the treatment of neurodegenerative diseases to avoid undesirable effects. In this study, we present a workflow for the identification and prioritization of compounds as potentially selective human nNOS inhibitors. Three-dimensional pharmacophore models were constructed based on a set of known nNOS inhibitors. The pharmacophore models were evaluated by Pareto surface and CoMFA (Comparative Molecular Field Analysis) analyses. The best pharmacophore model, which included 7 pharmacophore features, was used as a search query in the SPECS database (SPECS^®, Delft, The Netherlands). The hit compounds were further filtered by scoring and docking. Ten hits were identified as potential selective nNOS inhibitors. Full article

(This article belongs to the Special Issue Molecular Science for Drug Development and Biomedicine)

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Open AccessArticle

Inhibitory Effects of Palmultang on Inflammatory Mediator Production Related to Suppression of NF-κB and MAPK Pathways and Induction of HO-1 Expression in Macrophages

by You-Chang Oh, Yun Hee Jeong, Won-Kyung Cho, Min-Jung Gu and Jin Yeul Ma

Int. J. Mol. Sci. 2014, 15(5), 8443-8457; https://doi.org/10.3390/ijms15058443 - 13 May 2014

Cited by 17 | Viewed by 8229

Abstract

Palmultang (PM) is an herbal decoction that has been used to treat anorexia, anemia, general prostration, and weakness due to chronic illness since medieval times in Korea, China, and Japan. The present study focused on the inhibitory effects of PM on the production [...] Read more.

Palmultang (PM) is an herbal decoction that has been used to treat anorexia, anemia, general prostration, and weakness due to chronic illness since medieval times in Korea, China, and Japan. The present study focused on the inhibitory effects of PM on the production of inflammatory factors and on the activation of mechanisms in murine macrophages. PM suppressed the expression of nitric oxide (NO), inflammatory cytokines and inflammatory proteins by inhibiting nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signaling pathways and by inducing heme oxygenase (HO)-1 expression. Collectively, our results explain the anti-inflammatory effect and inhibitory mechanism of PM in macrophages stimulated with lipopolysaccharide (LPS). Full article

(This article belongs to the Special Issue Molecular Science for Drug Development and Biomedicine)

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Synthesis, Characterization and Anti-Breast Cancer Activity of New 4-Aminoantipyrine-Based Heterocycles

by Mostafa M. Ghorab, Marwa G. El-Gazzar and Mansour S. Alsaid

Int. J. Mol. Sci. 2014, 15(5), 7539-7553; https://doi.org/10.3390/ijms15057539 - 2 May 2014

Cited by 55 | Viewed by 7547

Abstract

4-Aminoantipyrine was utilized as key intermediate for the synthesis of pyrazolone derivatives bearing biologically active moieties. The newly synthesized compounds were characterized by IR, ¹H- and ¹³C-NMR spectral and microanalytical studies. The compounds were screened as anticancer agents against a human [...] Read more.

4-Aminoantipyrine was utilized as key intermediate for the synthesis of pyrazolone derivatives bearing biologically active moieties. The newly synthesized compounds were characterized by IR, ¹H- and ¹³C-NMR spectral and microanalytical studies. The compounds were screened as anticancer agents against a human tumor breast cancer cell line MCF7, and the results showed that (Z)-4-((3-amino-5-imino-1-phenyl-1H-pyrazol-4(5H)-ylidene)methylamino)-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-one 5, 3-(4-bromophenyl) -1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile 13, 1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-3-(4-iodophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile 14, 3,3′-(4,4′-sulfonylbis(4,1-phenylene))bis(1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile) 16, (Z)-1- (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-hydrazono-4-oxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carbonitrile 17, (Z)-1-(1,5-dimethyl-3-oxo-2-phenyl- 2,3-dihydro-1H-pyrazol-4-yl)-4-oxo-3-phenyl-2-(2-phenylhydrazono)-1,2,3,4-tetrahydro pyrimidine-5-carbonitrile 18, and (Z)-4-(3-amino-6-hydrazono-7-phenyl-6,7-dihydro pyrazolo[3,4-d]pyrimidin-5-yl)-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-one 19 were the most active compounds with IC₅₀ values ranging from 30.68 to 60.72 µM compared with Doxorubicin as positive control with the IC₅₀ value 71.8 µM. Full article

(This article belongs to the Special Issue Molecular Science for Drug Development and Biomedicine)

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Open AccessArticle

iNR-Drug: Predicting the Interaction of Drugs with Nuclear Receptors in Cellular Networking

by Yue-Nong Fan, Xuan Xiao, Jian-Liang Min and Kuo-Chen Chou

Int. J. Mol. Sci. 2014, 15(3), 4915-4937; https://doi.org/10.3390/ijms15034915 - 19 Mar 2014

Cited by 84 | Viewed by 9490

Abstract

Nuclear receptors (NRs) are closely associated with various major diseases such as cancer, diabetes, inflammatory disease, and osteoporosis. Therefore, NRs have become a frequent target for drug development. During the process of developing drugs against these diseases by targeting NRs, we are often [...] Read more.

Nuclear receptors (NRs) are closely associated with various major diseases such as cancer, diabetes, inflammatory disease, and osteoporosis. Therefore, NRs have become a frequent target for drug development. During the process of developing drugs against these diseases by targeting NRs, we are often facing a problem: Given a NR and chemical compound, can we identify whether they are really in interaction with each other in a cell? To address this problem, a predictor called “iNR-Drug” was developed. In the predictor, the drug compound concerned was formulated by a 256-D (dimensional) vector derived from its molecular fingerprint, and the NR by a 500-D vector formed by incorporating its sequential evolution information and physicochemical features into the general form of pseudo amino acid composition, and the prediction engine was operated by the SVM (support vector machine) algorithm. Compared with the existing prediction methods in this area, iNR-Drug not only can yield a higher success rate, but is also featured by a user-friendly web-server established at http://www.jci-bioinfo.cn/iNR-Drug/, which is particularly useful for most experimental scientists to obtain their desired data in a timely manner. It is anticipated that the iNR-Drug server may become a useful high throughput tool for both basic research and drug development, and that the current approach may be easily extended to study the interactions of drug with other targets as well. Full article

(This article belongs to the Special Issue Molecular Science for Drug Development and Biomedicine)

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Open AccessArticle

Structure of N-Terminal Sequence Asp-Ala-Glu-Phe-Arg-His-Asp-Ser of Aβ-Peptide with Phospholipase A₂ from Venom of Andaman Cobra Sub-Species Naja naja sagittifera at 2.0 Å Resolution

by Zeenat Mirza, Vikram Gopalakrishna Pillai and Wei-Zhu Zhong

Int. J. Mol. Sci. 2014, 15(3), 4221-4236; https://doi.org/10.3390/ijms15034221 - 10 Mar 2014

Cited by 3 | Viewed by 7905

Abstract

Alzheimer’s disease (AD) is one of the most significant social and health burdens of the present century. Plaques formed by extracellular deposits of amyloid β (Aβ) are the prime player of AD’s neuropathology. Studies have implicated the varied role of phospholipase A₂ [...] Read more.

Alzheimer’s disease (AD) is one of the most significant social and health burdens of the present century. Plaques formed by extracellular deposits of amyloid β (Aβ) are the prime player of AD’s neuropathology. Studies have implicated the varied role of phospholipase A₂ (PLA₂) in brain where it contributes to neuronal growth and inflammatory response. Overall contour and chemical nature of the substrate-binding channel in the low molecular weight PLA₂s are similar. This study involves the reductionist fragment-based approach to understand the structure adopted by N-terminal fragment of Alzheimer’s Aβ peptide in its complex with PLA₂. In the current communication, we report the structure determined by X-ray crystallography of N-terminal sequence Asp-Ala-Glu-Phe-Arg-His-Asp-Ser (DAEFRHDS) of Aβ-peptide with a Group I PLA₂ purified from venom of Andaman Cobra sub-species Naja naja sagittifera at 2.0 Å resolution (Protein Data Bank (PDB) Code: 3JQ5). This is probably the first attempt to structurally establish interaction between amyloid-β peptide fragment and hydrophobic substrate binding site of PLA₂ involving H bond and van der Waals interactions. We speculate that higher affinity between Aβ and PLA₂ has the therapeutic potential of decreasing the Aβ–Aβ interaction, thereby reducing the amyloid aggregation and plaque formation in AD. Full article

(This article belongs to the Special Issue Molecular Science for Drug Development and Biomedicine)

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Open AccessArticle

Perineural Dexmedetomidine Attenuates Inflammation in Rat Sciatic Nerve via the NF-κB Pathway

by Yan Huang, Yi Lu, Lei Zhang, Jia Yan, Jue Jiang and Hong Jiang

Int. J. Mol. Sci. 2014, 15(3), 4049-4059; https://doi.org/10.3390/ijms15034049 - 6 Mar 2014

Cited by 58 | Viewed by 8171

Abstract

Recent studies have shown that dexmedetomidine exerts an anti-inflammatory effect by reducing serum levels of inflammatory factors, however, the up-stream mechanism is still unknown. The transcription factor NF-κB enters the nucleus and promotes the transcription of its target genes, including those encoding the [...] Read more.

Recent studies have shown that dexmedetomidine exerts an anti-inflammatory effect by reducing serum levels of inflammatory factors, however, the up-stream mechanism is still unknown. The transcription factor NF-κB enters the nucleus and promotes the transcription of its target genes, including those encoding the pro-inflammatory cytokines IL-6 and TNF-α. In this study, we established a rat model that simulates a clinical surgical procedure to investigate the anti-inflammatory effect of perineural administration of dexmedetomidine and the underlying mechanism. Dexmedetomidine reduced the sciatic nerve levels of IL-6 and TNF-α at both the mRNA and protein level. Dexmedetomidine also inhibited the translocation of activated NF-κB to the nucleus and the binding activity of NF-κB. The anti-inflammatory effect is confirmed to be dose-dependent. Finally, pyrrolidine dithiocarbamate also reduced the levels of IL-6 and TNF-α and the activation of NF-κB. In conclusion, dexmedetomidine inhibited the nuclear translocation and binding activity of activated NF-κB, thus reducing inflammatory cytokines. Full article

(This article belongs to the Special Issue Molecular Science for Drug Development and Biomedicine)

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Open AccessArticle

Prediction of Protein–Protein Interaction with Pairwise Kernel Support Vector Machine

by Shao-Wu Zhang, Li-Yang Hao and Ting-He Zhang

Int. J. Mol. Sci. 2014, 15(2), 3220-3233; https://doi.org/10.3390/ijms15023220 - 21 Feb 2014

Cited by 50 | Viewed by 7644

Abstract

Protein–protein interactions (PPIs) play a key role in many cellular processes. Unfortunately, the experimental methods currently used to identify PPIs are both time-consuming and expensive. These obstacles could be overcome by developing computational approaches to predict PPIs. Here, we report two methods of [...] Read more.

Protein–protein interactions (PPIs) play a key role in many cellular processes. Unfortunately, the experimental methods currently used to identify PPIs are both time-consuming and expensive. These obstacles could be overcome by developing computational approaches to predict PPIs. Here, we report two methods of amino acids feature extraction: (i) distance frequency with PCA reducing the dimension (DFPCA) and (ii) amino acid index distribution (AAID) representing the protein sequences. In order to obtain the most robust and reliable results for PPI prediction, pairwise kernel function and support vector machines (SVM) were employed to avoid the concatenation order of two feature vectors generated with two proteins. The highest prediction accuracies of AAID and DFPCA were 94% and 93.96%, respectively, using the 10 CV test, and the results of pairwise radial basis kernel function are considerably improved over those based on radial basis kernel function. Overall, the PPI prediction tool, termed PPI-PKSVM, which is freely available at http://159.226.118.31/PPI/index.html, promises to become useful in such areas as bio-analysis and drug development. Full article

(This article belongs to the Special Issue Molecular Science for Drug Development and Biomedicine)

793 KiB

Open AccessArticle

iRSpot-TNCPseAAC: Identify Recombination Spots with Trinucleotide Composition and Pseudo Amino Acid Components

by Wang-Ren Qiu, Xuan Xiao and Kuo-Chen Chou

Int. J. Mol. Sci. 2014, 15(2), 1746-1766; https://doi.org/10.3390/ijms15021746 - 24 Jan 2014

Cited by 238 | Viewed by 11736

Abstract

Meiosis and recombination are the two opposite aspects that coexist in a DNA system. As a driving force for evolution by generating natural genetic variations, meiotic recombination plays a very important role in the formation of eggs and sperm. Interestingly, the recombination does [...] Read more.

Meiosis and recombination are the two opposite aspects that coexist in a DNA system. As a driving force for evolution by generating natural genetic variations, meiotic recombination plays a very important role in the formation of eggs and sperm. Interestingly, the recombination does not occur randomly across a genome, but with higher probability in some genomic regions called “hotspots”, while with lower probability in so-called “coldspots”. With the ever-increasing amount of genome sequence data in the postgenomic era, computational methods for effectively identifying the hotspots and coldspots have become urgent as they can timely provide us with useful insights into the mechanism of meiotic recombination and the process of genome evolution as well. To meet the need, we developed a new predictor called “iRSpot-TNCPseAAC”, in which a DNA sample was formulated by combining its trinucleotide composition (TNC) and the pseudo amino acid components (PseAAC) of the protein translated from the DNA sample according to its genetic codes. The former was used to incorporate its local or short-rage sequence order information; while the latter, its global and long-range one. Compared with the best existing predictor in this area, iRSpot-TNCPseAAC achieved higher rates in accuracy, Mathew’s correlation coefficient, and sensitivity, indicating that the new predictor may become a useful tool for identifying the recombination hotspots and coldspots, or, at least, become a complementary tool to the existing methods. It has not escaped our notice that the aforementioned novel approach to incorporate the DNA sequence order information into a discrete model may also be used for many other genome analysis problems. The web-server for iRSpot-TNCPseAAC is available at http://www.jci-bioinfo.cn/iRSpot-TNCPseAAC. Furthermore, for the convenience of the vast majority of experimental scientists, a step-by-step guide is provided on how to use the current web server to obtain their desired result without the need to follow the complicated mathematical equations. Full article

(This article belongs to the Special Issue Molecular Science for Drug Development and Biomedicine)

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Review

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976 KiB

Open AccessReview

Colonization and Infection of the Skin by S. aureus: Immune System Evasion and the Response to Cationic Antimicrobial Peptides

by Sunhyo Ryu, Peter I. Song, Chang Ho Seo, Hyeonsook Cheong and Yoonkyung Park

Int. J. Mol. Sci. 2014, 15(5), 8753-8772; https://doi.org/10.3390/ijms15058753 - 16 May 2014

Cited by 112 | Viewed by 18581

Abstract

Staphylococcus aureus (S. aureus) is a widespread cutaneous pathogen responsible for the great majority of bacterial skin infections in humans. The incidence of skin infections by S. aureus reflects in part the competition between host cutaneous immune defenses and S. aureus [...] Read more.

Staphylococcus aureus (S. aureus) is a widespread cutaneous pathogen responsible for the great majority of bacterial skin infections in humans. The incidence of skin infections by S. aureus reflects in part the competition between host cutaneous immune defenses and S. aureus virulence factors. As part of the innate immune system in the skin, cationic antimicrobial peptides (CAMPs) such as the β-defensins and cathelicidin contribute to host cutaneous defense, which prevents harmful microorganisms, like S. aureus, from crossing epithelial barriers. Conversely, S. aureus utilizes evasive mechanisms against host defenses to promote its colonization and infection of the skin. In this review, we focus on host-pathogen interactions during colonization and infection of the skin by S. aureus and methicillin-resistant Staphylococcus aureus (MRSA). We will discuss the peptides (defensins, cathelicidins, RNase7, dermcidin) and other mediators (toll-like receptor, IL-1 and IL-17) that comprise the host defense against S. aureus skin infection, as well as the various mechanisms by which S. aureus evades host defenses. It is anticipated that greater understanding of these mechanisms will enable development of more sustainable antimicrobial compounds and new therapeutic approaches to the treatment of S. aureus skin infection and colonization. Full article

(This article belongs to the Special Issue Molecular Science for Drug Development and Biomedicine)

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Other

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267 KiB

Open AccessTechnical Note

PseAAC-General: Fast Building Various Modes of General Form of Chou’s Pseudo-Amino Acid Composition for Large-Scale Protein Datasets

by Pufeng Du, Shuwang Gu and Yasen Jiao

Int. J. Mol. Sci. 2014, 15(3), 3495-3506; https://doi.org/10.3390/ijms15033495 - 26 Feb 2014

Cited by 251 | Viewed by 9776

Abstract

The general form pseudo-amino acid composition (PseAAC) has been widely used to represent protein sequences in predicting protein structural and functional attributes. We developed the program PseAAC-General to generate various different modes of Chou’s general PseAAC, such as the gene ontology mode, the [...] Read more.

The general form pseudo-amino acid composition (PseAAC) has been widely used to represent protein sequences in predicting protein structural and functional attributes. We developed the program PseAAC-General to generate various different modes of Chou’s general PseAAC, such as the gene ontology mode, the functional domain mode, and the sequential evolution mode. This program allows the users to define their own desired modes. In every mode, 544 physicochemical properties of the amino acids are available for choosing. The computing efficiency is at least 100 times that of existing programs, which makes it able to facilitate the extensive studies on proteins and peptides. The PseAAC-General is freely available via SourceForge. It runs on both Linux and Windows. Full article

(This article belongs to the Special Issue Molecular Science for Drug Development and Biomedicine)

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