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Combinatorial Chemistry & High Throughput Screening

Liqin Wang, Miao Xu, Noel Southall, Wei Zheng, Shuishu Wang
Tuberculosis (TB) still kills over 1.5 million people per year despite available anti-TB drugs. The emergence of drug-resistant TB poses a major threat to public health and prompts for an urgent need for new and more effective drugs. The long duration needed to treat TB by the current TB drugs, which target the essential cellular activities, inevitably leads to the emergence of drug-resistance. PhoP of Mycobacterium tuberculosis (MTB), an essential virulence factor, is a novel target for drug development. Guided by the crystal structure of the PhoP-DNA complex, we designed and developed a robust high-throughput screening assay for identification of PhoP inhibitors that disrupt the PhoP-DNA binding...
October 10, 2016: Combinatorial Chemistry & High Throughput Screening
Anna Ngo, Ann Koay, Christian Pecquet, Carmen C Diaconu, Yasmine Ould-Amer, Qiwei Huang, Congbao Kang, Anders Poulsen, May Ann Lee, David Jenkins, Andrew Shiau, Stefan N Constantinescu, Meng Ling Choo
BACKGROUND: Rather than a Janus Kinase 2 inhibitor (ruxolitinib), a specific thrombopoietin receptor (TpoR) inhibitor would be more specific for the treatment of myeloproliferative neoplasms due to TpoR mutations. OBJECTIVE: A cell-based phenotypic approach to identify specific TpoR inhibitors was implemented and a library of 505,483 small molecules was screened for inhibitory effects on cells transformed by TpoR mutants. RESULTS: Among the identified hits are two analogs of 3-(4-piperidinyl) indole...
October 10, 2016: Combinatorial Chemistry & High Throughput Screening
Sayyedmostafa Habibi-Khorassani, Mehdi Shahraki, Sayedeh Shadfar Pourpanah, Ebrahim Mollashahi, Shabnam Keshavarz
In this work, synthesis and the feasibility of utilizing a modern in situ spectroscopic method (UV-vis spectrophotometry) has been demonstrated in order to investigate the reaction kinetics between arylaldehydes, malononitrile and dimedone in a mixture of ethanol and water as solvent in the presence of caffeine as a biodegradable catalyst. Attempts for mechanistic insight into the synthesis of a derivative of 4H-tetrahydrobenzo[b]pyrans included spectral kinetics approaches which revealed specific limiting conditions...
October 6, 2016: Combinatorial Chemistry & High Throughput Screening
Mariana M Xavier, Gabriela Sehnem Heck, Maurício Boff de Avila, Nayara M Bernhardt Levin, Val Oliveira Pintro, Nathália Lemes Carvalho, Walter F Azevedo
BACKGROUND: Docking allows to predict ligand binding to proteins, since the 3D-structure for the target is available. Several docking studies have been carried out to identify potential ligands for drug targets. Many of these studies resulted in the leads that were later developed as drugs. OBJECTIVE: Our goal here is to describe the development of an integrated computational tool to assess docking accuracy and build new scoring functions to predict ligand-binding affinity...
September 27, 2016: Combinatorial Chemistry & High Throughput Screening
Rajan Kumar Pandey, Priyanka Prajapati, Sukriti Goyal, Abhinav Grover, Vijay Kumar Prajapati
BACKGROUND: Visceral leishmaniasis (VL) is a tropical neglected disease, which encounters poorest of poor people living in Asia, Africa and Latin America; causes the mortality of more than 30,000 people worldwide. The armamentarium for the treatment of VL cases is limited and continuously facing decreasing of efficacy for existing drugs. Ornithine decarboxylase (ODC) is one of the interesting drug targets in Leishmania donovani, due to its association with redox metabolism. OBJECTIVE: To search an antileishmanial compound showing the inhibitory effect against ornithine decarboxylase of Leishmania donovani Method: In this study, we have modelled the three dimensional structure of ODC using Phyre2 (Protein Homology/analog Y Recognition Engine V 2...
September 7, 2016: Combinatorial Chemistry & High Throughput Screening
Maryam Iman, Hamid Bakhtiari Kaboutaraki, Rahim Jafari, Seyed Ayoub Hosseini, Abolghasem Moghimi, Ali Khamesipour, Asghar Beigi Harchegani, Asghar Davood
Recently, anti-Leishmania activities have been shown by Selenocyanate derivatives. In this study, thirty five selenocyanate and diselenide compounds were subjected to docking studies and compared to Miltefosine and Edelfosine as reference drugs. Desired Selenocyanates are built using HyperChem program, docking calculation was performed on the crystal structure of Leishmania infantum trypanothione reductase. Based on the binding energy, all of the aryl rings were more potent than either Edelfosine or Miltefosine...
September 7, 2016: Combinatorial Chemistry & High Throughput Screening
Hoora Hashemi, Malihe Hasanzadeh, Massoud Amanlou
Rheumatoid Arthritis (RA) is a progressing autoimmune inflammatory disease of joint, hallmarked by inflammation, pain and atrophy of bones. Toll-like receptor 5 (TLR5) is a novel inflammatory mediator in RA, and TLR5 inhibitors are speculated to have a therapeutic potential for the treatment of RA. Here we applied fragment pharmacophore-based virtual screening to identify novel TLR5 ligands. Among compounds collected from Otava peptidomimetic compounds, Maybridge fragment and ZINC libraries, 3355 compounds were selected for docking into the flagellin-binding site of TLR5...
September 7, 2016: Combinatorial Chemistry & High Throughput Screening
Khalil Eskandari, Bahador Karami
Catalytic reaction between barbituric acid (or N,N-dimethyl barbituric acid), 4-hydroxycoumarin, and a wide range of aryl aldehydes by employing titanium dioxide nanowires (TiO2 NWs) is described which led efficiently to obtain 12 newly prepared products successfully. Starting materials in the presence of catalytic amounts of TiO2 NWs as a key factor were condensed together via three C-C bond formation to obtain target products. This procedure profits some advantages such as an efficient, environmental safety and high recyclability of nano-catalyst...
September 7, 2016: Combinatorial Chemistry & High Throughput Screening
Ramanathan Shylaja, Meganathan Chandrasekaran, Rengarajan Kavitha
C-Jun-N-terminal kinase -1 (JNK -1) is a seriene/threonine kinase protein and a member of mitogen activated protein family (MAP- Kinase). The activation of JNK-1 leads to cell proliferation, cell death, DNA repair and metabolism. Here, we generate an atom based 3D - QSAR model to find a potent JNK-1 inhibitor. Pharmacophores with pharmacophoric features as two hydrogen bond acceptors (A), one hydrogen bond donor (D), one hydrophobic (H) and one aromatic ring (R) are generated. Amongst the generated pharmacophore hypothesis, AADHR...
September 1, 2016: Combinatorial Chemistry & High Throughput Screening
Abdollah Javidan, Mohammadjavad Taghizadeh, Ayub Hosseini, Maryam Iman, Rahim Jafari
Fenobam is a non-competitive mGluR5 antagonist as an anxiolytic agent. In this research a new series of fenobam analogues containing thiazole moiety instead of imidazole ring were designed and synthesized. The ureido-substituted products were synthesized from reaction of amino thiazole derivatives and isocyanate derivatives in dichloromethane solvent under microwave and ultrasonic irradiation condition. The synthesized compounds structures were established by means of IR, 1HNMR, 13CNMR spectroscopic data. Then, docking calculations were performed on the active site of mGLuR5 and compared to Fenobam as a reference drug by using AutoDock program...
August 31, 2016: Combinatorial Chemistry & High Throughput Screening
Yulin Zhang, Kebo Lv, Yulin Dong, Jionglong Su
In this research, networks of experimental and control groups from gene expression profiles are reversely modeled. By calculating the mutual information between genes, the gene networks are constructed with mutual information values as edge weights under thresholds. Four structural statistics of networks including node degree, clustering coefficient, shortest path length and standard betweenness centrality are used to analyze gene networks for breast cancer tissues in different grades and estrogen receptor (ER) states and comparing them with those for normal breast tissues...
August 31, 2016: Combinatorial Chemistry & High Throughput Screening
Neydeli Ayala-Mendivil, María de Los Angeles Calixto-Romo, Lorena Amaya-Delgado, Leticia Casas-Godoy, Georgina Sandoval
High throughput screening (HTS) is a powerful tool in biotechnology. The search for new or improved enzymes with suitable biochemical properties for industrial processes, has resulted in high efforts and research activities to develop new methodologies for activity screening. In this context, important advances have been achieved for the screening of cellulases and xylanases activities from wild and recombinant microorganisms, and from sequence databases. These enzymes have a wide range of industrial applications, including food, animal feed, textile, pulp and paper industries and detergents...
August 10, 2016: Combinatorial Chemistry & High Throughput Screening
Sanal Dev, Sunil R Dhaneshwar, Bijo Mathew
Camptothecin is a quinolone containing alkaloid isolated from the Chinese tree Camptotheca acuminate and exhibited its cytotoxicity activity by the inhibition of nuclear enzyme topoisomerase I (topo I). Camptothecin and its analogs binds with topo I and DNA complex form, which can arrest the tumor growth by interfering the various transactions mechanism of DNA. Besides its strong anticancer potential, the low solubility as well as instability of the hydroxylactone ring (Ring E) limits the clinical application Camptothecin...
August 10, 2016: Combinatorial Chemistry & High Throughput Screening
Rong You, Lu Zhou, Liangliang Zhong, Xiaoli Li, Suwn Zhou, Yahui Tian
Anaplastic lymphoma kinase, an insulin receptor protein-tyrosine kinase, is a very attractive receptor protein target for anticancer therapy. Pharmacophore hypotheses modeling, virtual screening and molecular docking were used to detect potential inhibitors of anaplastic lymphoma kinase in this paper. After the generation of ten pharmacophore hypotheses, Hypo1 with the highest correlation value (0.981), lowest RMS (0.565), highest cost difference (83.850) along with four typical chemical features was regarded as the best hypothesis...
August 1, 2016: Combinatorial Chemistry & High Throughput Screening
Preeti Patel, Avineesh Singh, Vijay Patel, Deepak K Jain, Ravichandran Veerasamy, Harish Rajak
Histone deacetylase inhibitors (HDACIs) can reactivate gene expression and inhibit the growth and survival of cancer cells. The 3D-QSAR and Pharmacophore modeling studies were performed to identify important pharmacophoric features and correlate 3D-chemical structure with biological activity. The pharmacophore hypotheses were developed using e-pharmacophore script and phase module. Pharmacophore hypothesis represents the 3D arrangement of molecular features necessary for activity. A series of 55 compounds with well-assigned HDAC inhibitory activity was used for 3D-QSAR model development...
August 1, 2016: Combinatorial Chemistry & High Throughput Screening
Mariya A Toropova, Ivan Raška, Andrey A Toropov, Mária Rašková
Quantitative structure - activity relationships (QSARs) are built up for three endpoints (i) blood-brain barrier permeability; (ii) butyrylcholinesterase (BChE) inhibitory activity; and (iii) for biological effect of antibacterial drugs. The models are based on utilization of the Monte Carlo technique. The CORAL software available on the Internet has been utilized for the calculations. The principles of validation of models together with principles of selection of potential therapeutic agents are suggested...
July 25, 2016: Combinatorial Chemistry & High Throughput Screening
Debarati Choudhury, Anupam Das Talukdar, Pankaj Chetia, Amitabha Bhattacharjee, Manabendra Dutta Choudhury
AIM AND OBJECTIVE: Overexpression of efflux pumps belonging to the Resistance Nodulation cell Division (RND) family is the most important intrinsic resistance mechanism of Pseudomonas aeruginosa. Hence, it is imperative to identify suitable efflux pump inhibitors (EPI) that can lead to increased intracellular concentration of antibiotics by blocking the pump. This study was undertaken to identify a putative plant based efflux pump inhibitor for RND efflux pump of P. aeruginosa. MATERIAL AND METHOD: Using molecular docking approach, 328 secondary plant metabolites have been screened for their inhibitory activity against cytoplasmic exporter protein MexB of MexAB-OprM efflux pump of P...
July 20, 2016: Combinatorial Chemistry & High Throughput Screening
Fatemeh Sheikholeslami-Farahani, Sobhan Rezayati, Zinatossadat Hossaini, Rahimeh Hajinasiri, Saeed Afshari Sharif Abada
A convenient procedure for preparation 1-(1-Propylsulfonic)-3-methylimidazolium thiocyanate as a novel Brønsted acidic ionic liquid thiocyanation agent and highly efficient heterogeneous catalytic is describes. This catalyst is used in regioselective thiocyanation of indoles, anilines, pyrroles and their derivatives (aromatic and heteroaromatic organic compounds) in the presence of H2O2 as a mild and oxidant in EtOH:H2O (1:1 v/v). These reactions performed under mild and simple conditions and give regioselective products in high yields and short reaction time...
July 9, 2016: Combinatorial Chemistry & High Throughput Screening
Feroz Khan, Pooja Sharma, Om Prakash, Aparna Shukla, Prema G Vasudev, Suaib Luqman, Santosh Kumar Srivastava
O. sanctum L. (O. tenuiflorum) is an important sacred medicinal plant of India known as Holy Basil or Tulsi. The chemical composition of volatile oil is highly complex and comprises high ratio of phenylpropanoids and terpenes, and some phenolic compound or flavonoids such as orientin and vicenin. These minor flavonoids known to be antioxidant and anticancer in nature. Orientin reported as potential anticancer agent due to anti-proliferative activity on human liver cancer cell line HepG2, but its mechanism of action are not fully explored...
July 9, 2016: Combinatorial Chemistry & High Throughput Screening
Jun Zhang, Xin Liu, Shu-Qing Wang, Jing-Wei Fu, Wei-Ren Xu, Xian-Chao Cheng, Run-Ling Wang
Rosiglitazone was restricted clinically due to the side effects such as edema, weight gain and cardiac failure mainly attributing to the single and selective PPARγ activation. Nowadays, multi-targeted PPARs agonists remained to be a hot topic in the antidiabetic medicinal chemistry field. In this paper, the cooperative PPARα/γ dual agonists were screened from Specs database via the flow chart of docking, ADMET prediction and molecular dynamics (MD) simulations. Representative compounds ZINC36517927 and ZINC13573581 displayed higher binding scores, better pharmacokinetic profiles and were predicted to display the best binding affinity with PPARα/γ...
June 14, 2016: Combinatorial Chemistry & High Throughput Screening
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