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ADME in silico

Loredana Salerno, Emanuele Amata, Giuseppe Romeo, Agostino Marrazzo, Orazio Prezzavento, Giuseppe Floresta, Valeria Sorrenti, Ignazio Barbagallo, Antonio Rescifina, Valeria Pittalà
Here we report the design, synthesis, and molecular modeling of new potent and selective imidazole-based HO-1 inhibitors in which the imidazole nucleus and the hydrophobic groups are linked by a phenylethanolic spacer. Most of the tested compounds showed a good inhibitor activity with IC 50 values in the low micromolar range, with two of them (1b and 1j) exhibiting also high selectivity toward HO-2. These results were obtained by the idea of potholing the entire volume of the principal hydrophobic western region with an appropriate ligand volume...
February 9, 2018: European Journal of Medicinal Chemistry
Haobin Cai, Yunxia Luo, Xin Yan, Peng Ding, Yujie Huang, Shuhuan Fang, Rong Zhang, Yunbo Chen, Zhouke Guo, Jiansong Fang, Qi Wang, Jun Xu
Bushen-Yizhi prescription (BSYZ) has been an effective traditional Chinese medicine (TCM) prescription in treating Alzheimer's disease (AD) for hundreds of years. However, the underlying mechanisms have not been fully elucidated yet. In this work, a systems pharmacology approach was developed to reveal the underlying molecular mechanisms of BSYZ in treating AD. First, we obtained 329 candidate compounds of BSYZ by in silico ADME/T filter analysis and 138 AD-related targets were predicted by our in-house WEGA algorithm via mapping predicted targets into AD-related proteins...
February 15, 2018: Scientific Reports
Archana S Gurjar, Mrunali N Darekar, Keng Yoon Yeong, Luyi Ooi
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with multiple factors associated with its pathogenesis. Our strategy against AD involves design of multi-targeted 2-substituted-4,5-diphenyl-1H-imidazole analogues which can interact and inhibit AChE, thereby, increasing the synaptic availability of ACh, inhibit BuChE, relieve induced oxidative stress and confer a neuroprotective role. Molecular docking was employed to study interactions within the AChE active site. In silico ADME study was performed to estimate pharmacokinetic parameters...
February 2, 2018: Bioorganic & Medicinal Chemistry
Flávia Pereira Dias Viegas, Matheus de Freitas Silva, Miguel Divino da Rocha, Maísa Rosa Castelli, Mariana Máximo Riquiel, Rafael Pereira Machado, Sarah Macedo Vaz, Laís Medeiros Simões de Lima, Karla Cristine Mancini, Patrícia Cruz Marques de Oliveira, Élida Parreira Morais, Vanessa Silva Gontijo, Fernanda Motta R da Silva, Dora D'Alincourt da Fonseca Peçanha, Newton Gonçalves Castro, Gilda A Neves, Alexandre Giusti-Paiva, Fabiana Cardoso Vilela, Lidiane Orlandi, Ihosvany Camps, Márcia Paranho Veloso, Luis Felipe Leomil Coelho, Marisa Ionta, Guilherme Álvaro Ferreira-Silva, Rodrigo Machado Pereira, Laurent E Dardenne, Isabella Alvim Guedes, Wellerson de Oliveira Carneiro Junior, Paula Maria Quaglio Bellozi, Antônio Carlos Pinheiro de Oliveira, Fábio Furlan Ferreira, Letizia Pruccoli, Andrea Tarozzi, Claudio Viegas
A new series of sixteen multifunctional N-benzyl-piperidine-aryl-acylhydrazones hybrid derivatives was synthesized and evaluated for multi-target activities related to Alzheimer's disease (AD). The molecular hybridization approach was based on the combination, in a single molecule, of the pharmacophoric N-benzyl-piperidine subunit of donepezil, the substituted hydroxy-piperidine fragment of the AChE inhibitor LASSBio-767, and an acylhydrazone linker, a privileged structure present in a number of synthetic aryl- and aryl-acylhydrazone derivatives with significant AChE and anti-inflammatory activities...
January 31, 2018: European Journal of Medicinal Chemistry
Mire Zloh, Stewart B Kirton
The research into the use of small molecules as drugs continues to be a key driver in the development of molecular databases, computer-aided drug design software and collaborative platforms. The evolution of computational approaches is driven by the essential criteria that a drug molecule has to fulfill, from the affinity to targets to minimal side effects while having adequate absorption, distribution, metabolism, and excretion (ADME) properties. A combination of ligand- and structure-based drug development approaches is already used to obtain consensus predictions of small molecule activities and their off-target interactions...
January 30, 2018: Future Medicinal Chemistry
Avneet Kaur, Dharam P Pathak, Vidushi Sharma, Sharad Wakode
A new series of substituted-N-(3,4-dimethoxyphenyl)-benzoxazole derivatives 13a-13p was synthesized and evaluated in vitro for their COX (I and II) inhibitory activity, in vivo anti-inflammatory and ulcerogenic potential. Compounds 13d, 13h, 13k, 13l and 13n exhibited significant COX-2 inhibitory activity and selectivity towards COX-2 over COX-1. These selected compounds were screened for their in vivo anti-inflammatory activity by carrageenan induced rat paw edema method. Among these compounds, 13d was the most promising analogs of the series with percent inhibition of 84...
January 11, 2018: Bioorganic & Medicinal Chemistry
Aicha Laoud, Fouad Ferkous, Laura Maccari, Giorgio Maccari, Youcef Saihi, Khaireddine Kraim
In this study, a virtual screening procedure was applied to identify new potential nt-MGAM inhibitors as a possible medication for type 2 diabetes. To this aim, a series of salacinol analogues were first investigated by docking analysis for their binding to the X-ray structure of the biological target nt-MGAM. Key interactions for ligand binding into the receptor active site were identified which shared common features to those found for other known inhibitors, which strengthen the results of this study. 3D QSAR model was then built and showed to be statistically significant and with a good predictive power for the training (R2 = 0...
December 12, 2017: Computational Biology and Chemistry
Sanjeev R Patil, Satyanarayana Bollikonda, Rajendra H Patil, Jaiprakash N Sangshetti, Anil S Bobade, Ashish Asrondkar, Padi Pratap Reddy, Devanand B Shinde
A series of 5-substitutedbenzylideneamino-2-butylbenzofuran-3-yl-4-methoxyphenyl methanones is synthesized and evaluated for antileishmanial and antioxidant activities. Compounds 4f (IC50 = 52.0 ± 0.09 µg/ml), 4h (IC50 = 56.0 ± 0.71 µg/ml) and 4l (IC50 = 59.3 ± 0.55 µg/ml) were shown significant antileishmanial when compared with standard sodium stibogluconate (IC50 = 490.0 ± 1.5 µg/ml). Antioxidant study revealed that compounds 4i (IC50 = 2.44 ± 0.47 µg/ml) and 4l (IC50 = 3...
December 8, 2017: Bioorganic & Medicinal Chemistry Letters
Shivani Kumar, Suman Chowdhury, Suresh Kumar
BACKGROUND: Alzheimer's disease (AD) is the most prevalent form of dementia and represents one of the highest unmet requirements in medicine today. There is shortage of novel molecules entering into market because of poor pharmacokinetic properties and safety issues. Drug repurposing offers an opportunity to reinvigorate the slowing drug discovery process by finding new uses for existing drugs. The major advantage of the drug repurposing approach is that the safety issues are already investigated in the clinical trials and the drugs are commercially available in the marketplace...
October 27, 2017: BMC Neuroscience
Sajad Shahbazi, Jagdeep Kaur, Ananya Kuanar, Dattatreya Kar, Shikha Singh, Ranbir Chander Sobti
Alzheimer's disease (AD), a worldwide renowned progressive neurodegenerative disorder, is the most common cause of dementia. There are several studies on the important role of cholesterol metabolism in AD pathogenesis, which indicated that the high concentrations of serum cholesterol increase the risk of AD. Biosynthesis of the plasma cholesterol and other isoprenoids is catalyzed by 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) through the conversion of HMG-CoA to mevalonic acid in mevalonate pathway. Normally, the high level of plasma cholesterol is downregulated by HGMCR inhibition as the result of degradation of LDL, but in abnormal conditions, for example, high blood glucose, the HMGCR over activated resulting in uncontrolled blood cholesterol...
October 2017: Assay and Drug Development Technologies
Syed Mobasher Ali Abid, Hafiza Amna Younus, Mariya Al-Rashida, Zunaira Arshad, Tooba Maryum, Mazhar Amjad Gilani, Abdulrahman I Alharthi, Jamshed Iqbal
A series of sulfonyl hydrazones derived from 3-formylchromone was synthesized and discovered to be effective, non-selective inhibitors of monoamine oxidases (MAO-A and MAO-B). The compounds are easily (synthetically) accessible in high yields, by simple condensation of 4-methylbenzenesulfonohydrazide with different (un)substituted 3-formylchromones. All compounds had IC50 values in lower micro-molar range (IC50 = 0.33-7.14 μM for MAO-A, and 1.12-3.56 μM for MAO-B). The most active MAO-B inhibitor was N'-[(E)-(6-fluoro-4-oxo-4H-chromen-3-yl)methylidene]-4-methylbenzenesulfonohydrazide (3e) with IC50 value of 1...
October 4, 2017: Bioorganic Chemistry
Merilin Al Sharif, Petko Alov, Vessela Vitcheva, Antonia Diukendjieva, Mattia Mori, Bruno Botta, Ivanka Tsakovska, Ilza Pajeva
Nonalcoholic fatty liver disease (NAFLD) is considered to be the most common chronic liver disease. The discovery of natural product-based NAFLD modulators requires a more comprehensive study of their modes of action (MoAs). In this study we analysed available in the literature data for 26 naturally-derived compounds associated with experimental evidence for NAFLD alleviation and outlined potential biomolecular targets and a network of pharmacological MoAs for 12 compounds with the highest number of experimentally supported MoA key events, modulated by them...
December 15, 2017: Toxicology and Applied Pharmacology
Tuleshwori Devi Sapam, Anbumani Velmurugan Ilavarasi, Bhagath Kumar Palaka, Elakkiya Elumalai, Nirmala Devi Kanika, Dinakara Rao Ampasala
Mammalian lethal with SEC13 protein 8 (mLST8), is an indispensable protein subunit of mammalian target of rapamycin (mTOR) signaling pathway that interacts with the kinase domain of mTOR protein, thereby stabilizing its active site. Experimental studies reported the over expression of mLST8 in human colon and prostate cancers by activation of both mTORC1/2 complexes and subsequent downstream substrates leading to tumor progression. Considering its role, targeting mLST8 protein would be a therapeutic approach against tumor progression in colon and prostate cancers...
October 17, 2017: Journal of Receptor and Signal Transduction Research
Saeed Alqahtani
Although significant progress has been made in high-throughput screening of absorption, distribution, metabolism and excretion, and toxicity (ADME-Tox) properties in drug discovery and development, in silico ADME-Tox prediction continues to play an important role in facilitating the appropriate selection of candidate drugs by pharmaceutical companies prior to expensive clinical trials. Areas covered: This review provides an overview of the available in silico models that have been used to predict the ADME-Tox properties of compounds...
November 2017: Expert Opinion on Drug Metabolism & Toxicology
David Lagorce, Lina Bouslama, Jerome Becot, Maria A Miteva, Bruno O Villoutreix
Motivation: Identification of small molecules that could be interesting starting points for drug discovery or to investigate a biological system as in chemical biology endeavours is both time consuming and costly. In silico approaches that assist the design of quality compound collections or help to prioritize molecules before synthesis or purchase are therefore valuable. Here quality refers to the selection of molecules that pass one or several selected filters that can be tuned by the users according to the project and the stage of the project...
November 15, 2017: Bioinformatics
Giuseppe Floresta, Venerando Pistarà, Emanuele Amata, Maria Dichiara, Arcangelo Damigella, Agostino Marrazzo, Orazio Prezzavento, Francesco Punzo, Antonio Rescifina
In this paper, we investigated the hypothesis that pseudouridine isoxazolidinyl nucleoside analogues could act as potential inhibitors of the pseudouridine 5'-monophosphate glycosidase. This purpose was pursued using molecular modeling and in silico ADME-Tox profiling. From these studies emerged that the isoxazolidinyl derivative 1 5'-monophosphate can be effectively accommodated within the active site of the enzyme with a ligand efficiency higher than that of the natural substrate. In this context, the poor nucleofugality of the N-protonated isoxazolidine prevents or slows down, the first mechanistic step proposed for the degradation of the pseudouridine 5'-monophosphate glycosidase, leading to the enzyme inhibition...
September 22, 2017: Chemical Biology & Drug Design
Xu Wang, Suyun Yu, Qi Jia, Lichuan Chen, Jinqiu Zhong, Yanhong Pan, Peiliang Shen, Yin Shen, Siliang Wang, Zhonghong Wei, Yuzhu Cao, Yin Lu
NiaoDuQing (NDQ) granules, a traditional Chinese medicine, has been clinically used in China for over fourteen years to treat chronic kidney disease (CKD). To elucidate the mechanisms underlying the therapeutic benefits of NDQ, we designed an approach incorporating chemoinformatics, bioinformatics, network biology methods, and cellular and molecular biology experiments. A total of 182 active compounds were identified in NDQ granules, and 397 putative targets associated with different diseases were derived through ADME modelling and target prediction tools...
August 22, 2017: Oncotarget
Antonino Lauria, Francesco Mingoia, Aída Nelly García-Argáez, Riccardo Delisi, Annamaria Martorana, Lisa Dalla Via
Due to the scarce biological profile, the pyrazolo[1,2-a]benzo[1,2,3,4]tetrazine-3-one scaffold (PBT) has been recently explored as promising core for potential anticancer candidates. Several suitably decorated derivatives (PBTs) exhibited antiproliferative activity in the low-micromolar range associated with apoptosis induction and cell cycle arrest on S phase. Herein, we selected the most active derivatives and submitted them to further biological explorations to deepen the mechanism of action. At first, a DNA targeting is approached by means of flow Linear Dichroism experiments so as to evaluate how small planar molecules might interact with DNA, including the interference with the catalytic cycle of topoisomerase II and the influence on the cleavable complex stabilization (poisoning effect)...
September 14, 2017: Chemical Biology & Drug Design
Pulicherla Yugandhar, Konidala Kranthi Kumar, Pabbaraju Neeraja, Nataru Savithramma
AIM: This study aims to isolate, characterize, and in silico evaluate of anticancer polyphenols from different parts of Syzygium alternifolium. MATERIALS AND METHODS: The polyphenols were isolated by standard protocol and characterized using Fourier-transform infrared (FT-IR), High performance liquid chromatography - Photodiode array detector coupled with Electrospray ionization - mass spectrometry (MS/MS). The compounds were elucidated based on retention time and molecular ions (m/z) either by [M+H](+)/[M-H](-) with the comparison of standard phenols as well as ReSpect software tool...
July 2017: Journal of Intercultural Ethnopharmacology
Sujay Laskar, Luis Sánchez-Sánchez, Manuel López-Ortiz, Hugo López-Muñoz, María L Escobar-Sánchez, Arturo T Sánchez, Ignacio Regla
Identification of a new class of antitumor agent capable to induce apoptosis without triggering necrotic cell death event is challenging. The present communication describes the multicomponent synthesis of seven new (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamates and their in vitro antiproliferative activity on cervical cancer cell line (CaSki), breast cancer cell line (MDA-MB231), lung cancer cell line (SK-Lu-1) and human lymphocytes. Among the synthesized dithiocarbamates, compound 9e displayed significant antiproliferative activity without inducing any necrotic cell death (both on tumour cells and lymphocytes) and induced apoptosis in tumor cells by the caspase dependent apoptotic pathway...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
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