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ADME in silico

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https://www.readbyqxmd.com/read/29041842/identifying-novel-small-molecule-antagonists-for-mlst8-protein-using-computational-approaches
#1
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
https://www.readbyqxmd.com/read/28988506/in-silico-adme-tox-modeling-progress-and-prospects
#2
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...
October 9, 2017: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/28961788/faf-drugs4-free-adme-tox-filtering-computations-for-chemical-biology-and-early-stages-drug-discovery
#3
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 endeavors 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...
July 29, 2017: Bioinformatics
https://www.readbyqxmd.com/read/28941159/molecular-modeling-studies-of-pseudouridine-isoxazolidinyl-nucleoside-analogues-as-potential-inhibitors-of-the-pseudouridine-5-monophosphate-glycosidase
#4
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
https://www.readbyqxmd.com/read/28915563/niaoduqing-granules-relieve-chronic-kidney-disease-symptoms-by-decreasing-renal-fibrosis-and-anemia
#5
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
https://www.readbyqxmd.com/read/28905525/new-insights-into-the-mechanism-of-action-of-pyrazolo-1-2-a-benzo-1-2-3-4-tetrazin-3-one-derivatives-endowed-with-anticancer-potential
#6
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
https://www.readbyqxmd.com/read/28894629/isolation-characterization-and-in-silico-docking-studies-of-synergistic-estrogen-receptor-a-anticancer-polyphenols-from-syzygium-alternifolium-wt-walp
#7
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
https://www.readbyqxmd.com/read/28868930/multicomponent-synthesis-of-some-new-1s-4s-2-5-diazabicyclo-2-2-1-heptane-dithiocarbamates-and-their-in-vitro-anti-proliferative-activity-against-caski-mda-mb-231-and-sk-lu-1-tumour-cells-as-apoptosis-inducing-agents-without-necrosis
#8
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
https://www.readbyqxmd.com/read/28865321/in-silico-identification-of-inhibitors-of-ribose-5-phosphate-isomerase-from-trypanosoma-cruzi-using-ligand-and-structure-based-approaches
#9
Vanessa de V C Sinatti, Luiz Phillippe R Baptista, Marcelo Alves-Ferreira, Laurent Dardenne, João Hermínio Martins da Silva, Ana Carolina Guimarães
Chagas disease, caused by the protozoan Trypanosoma cruzi, affects approximately seven million people, mainly in Latin America, and causes about 7000 deaths annually. The available treatments are unsatisfactory and search for more effective drugs against this pathogen is critical. In this context, the ribose 5-phosphate isomerase (Rpi) enzyme is a potential drug target mainly due to its function in the pentose phosphate pathway and its essentiality (previously shown in other trypanosomatids). In this study, we propose novel potential inhibitors for the Rpi of T...
August 12, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28803043/structure-based-development-of-novel-triazoles-and-related-thiazolotriazoles-as-anticancer-agents-and-cdc25a-b-phosphatase-inhibitors-synthesis-in%C3%A2-vitro-biological-evaluation-molecular-docking-and-in-silico-adme-t-studies
#10
Sherif A F Rostom, Mona H Badr, Heba A Abd El Razik, Hayam M A Ashour
Synthesis of twenty nine new 1,2,4-triazoles and some derived thiazolothiadiazoles (structurally-relevant to some reported triazoles with anticancer and/or Cdc25A/B inhibitory activities) is described in this study. The obtained NCI's in vitro antitumor data revealed that five analogs (12, 15, 18, 19 and 22) displayed considerable tumor percentage growth inhibitory activity (GI%), among which the analog 18 possessed a special antitumor potential and spectrum. Additionally, the same five analogs showed a marginal GI effect on the normal breast epithelial cell line MCF-10A indicating higher selectivity towards cancer cells...
October 20, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28802226/taraxerol-a-pentacyclic-triterpenoid-from-abroma-augusta-leaf-attenuates-diabetic-nephropathy-in-type-2-diabetic-rats
#11
Ritu Khanra, Niloy Bhattacharjee, Tarun K Dua, Ashis Nandy, Achintya Saha, Jatin Kalita, Prasenjit Manna, Saikat Dewanjee
Persistent hyperglycaemia coupled with inflammation plays an important role in the pathogenesis of diabetic nephropathy (DN). Present study examined the therapeutic potential of taraxerol isolated from the methanol extract of Abroma augusta leaf against DN using rodent model of type 2 diabetes (T2D). T2D was experimentally induced by high fat diet and a single low-single dose of streptozotocin (35mg/kg, i.p.). Accumulation of serum creatinine, urea, and uric acid, activation of lactate dehydrogenase and creatinin kinase, and release of urinary albumin represented the glomerular damage and the progression of nephropathy in T2D rats...
October 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28796406/diarylpyrazole-ligated-dihydropyrimidine-hybrids-as-potent-non-classical-antifolates-and-their-efficacy-against-plasmodium-falciparum
#12
Jaimin D Bhatt, Chaitanya J Chudasama, Kanuprasad D Patel
A series of diarylpyrazole clubbed dihydropyrimidine derivatives (J1-J30) was synthesized under microwave-assisted heating conditions by employing Biginelli reaction methodology and utilizing triethylammonium acetate both as a catalyst and as reaction medium, leading towards a greener reaction pathway. The synthesized entities were screened for their antimalarial efficacy against a Plasmodium falciparum strain in vitro. The active entities (J9, J15, J21, J25, and J27) obtained out of the in vitro screening were further evaluated for their enzyme inhibitory potency against the Pf-DHFR enzyme in vitro as well as in silico using Glide...
August 10, 2017: Archiv der Pharmazie
https://www.readbyqxmd.com/read/28758238/design-synthesis-and-docking-study-of-pyrimidine-triazine-hybrids-for-gaba-estimation-in-animal-epilepsy-models
#13
Meeta Sahu, Nadeem Siddiqui, Mohd Javed Naim, Ozair Alam, Mohammad Shahar Yar, Vidushi Sharma, Sharad Wakode
A series of new pyrimidine-triazine hybrids (4a-t) was designed and synthesized, from which potent anticonvulsant agents were identified. Most of the compounds exhibited promising anticonvulsant activity against the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests, along with minimal motor impairment with higher safety compared to the standard drugs, phenytoin and carbamazepine. In the series, 5-(4-(4-fluorophenyl)-6-(4-hydroxyphenyl)-2-thioxo-5,6-dihydropyrimidin-1(2H)-yl)-1,2-dihydro-1,2,4-triazin-3(6H)-one (4o) and 5-(6-(4-hydroxy-3-methoxyphenyl)-4-(4-hydroxyphenyl)-2-thioxo-5,6-dihydropyrimidin-1(2H)-yl)-1,2-dihydro-1,2,4-triazin-3(6H)-one (4s) emerged as most potent anticonvulsant agents with median doses of 22...
July 31, 2017: Archiv der Pharmazie
https://www.readbyqxmd.com/read/28746940/comparison-of-the-skin-penetration-of-3-metabolically-stable-chemicals-using-fresh-and-frozen-human-skin
#14
Carine Jacques-Jamin, Hélène Duplan, Helga Rothe, Ophelie Vaillant, Joan Eilstein, Sebastien Grégoire, Richard Cubberley, Daniela Lange, Corie Ellison, Martina Klaric, Nicola Hewitt, Andreas Schepky
BACKGROUND: The Cosmetics Europe ADME Task Force is developing in vitro and in silico tools for predicting skin and systemic concentrations after topical application of cosmetic ingredients. There are conflicting reports as to whether the freezing process affects the penetration of chemicals; therefore, we evaluated whether the storage of human skin used in our studies (8-12 weeks at -20°C) affected the penetration of model chemicals. METHODS: Finite doses of trans-cinnamic acid (TCA), benzoic acid (BA), and 6-methylcoumarin (6MC) (non-volatile, non-protein reactive and metabolically stable in skin) were applied to fresh and thawed frozen skin from the same donors...
2017: Skin Pharmacology and Physiology
https://www.readbyqxmd.com/read/28743970/adme-space-a-new-tool-for-medicinal-chemists-to-explore-adme-properties
#15
Giovanni Bocci, Emanuele Carosati, Philippe Vayer, Alban Arrault, Sylvain Lozano, Gabriele Cruciani
We introduce a new chemical space for drugs and drug-like molecules, exclusively based on their in silico ADME behaviour. This ADME-Space is based on self-organizing map (SOM) applied to 26,000 molecules. Twenty accurate QSPR models, describing important ADME properties, were developed and, successively, used as new molecular descriptors not related to molecular structure. Applications include permeability, active transport, metabolism and bioavailability studies, but the method can be even used to discuss drug-drug interactions (DDIs) or it can be extended to additional ADME properties...
July 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28708399/development-and-validation-of-a-computational-model-ensemble-for-the-early-detection-of-bcrp-abcg2-substrates-during-the-drug-design-stage
#16
Melisa E Gantner, Roxana N Peroni, Juan F Morales, María L Villalba, María E Ruiz, Alan Talevi
Breast Cancer Resistance Protein (BCRP) is an ATP-dependent efflux transporter linked to the multidrug resistance phenomenon in many diseases such as epilepsy and cancer and a potential source of drug interactions. For these reasons, the early identification of substrates and nonsubstrates of this transporter during the drug discovery stage is of great interest. We have developed a computational nonlinear model ensemble based on conformational independent molecular descriptors using a combined strategy of genetic algorithms, J48 decision tree classifiers, and data fusion...
August 28, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28694764/2-pyrazoline-derivatives-in-neuropharmacology-synthesis-adme-prediction-molecular-docking-and-in-vivo-biological-evaluation
#17
Savita Upadhyay, Avinash C Tripathi, Sarvesh Paliwal, Shailendra K Saraf
A novel series of 1,3,5-trisubstituted-2-pyrazoline derivatives (PFC-1 to PFC-16) were synthesized in a three step reaction using conventional and microwave assisted green chemistry approach. The synthesized derivatives were characterized and their chemical structures were established by various physicochemical methods such as IR, Mass, (1)H-NMR, (13)C-NMR and elemental analysis. The synthesized compounds were tested for their neuropharmacological potential. The compounds exhibited significant antidepressant and anti-anxiety activities against various behavioral in vivo models...
2017: EXCLI journal
https://www.readbyqxmd.com/read/28693910/antileishmanial-potential-of-fused-5-pyrazin-2-yl-4h-1-2-4-triazole-3-thiols-synthesis-biological-evaluations-and-computational-studies
#18
Sanjeev R Patil, Ashish Asrondkar, Vrushali Patil, Jaiprakash N Sangshetti, Firoz A Kalam Khan, Manoj G Damale, Rajendra H Patil, Anil S Bobade, Devanand B Shinde
A series of newer 1,2,4-triazole-3-thiol derivatives 5(a-m) and 6(a-i) containing a triazole fused with pyrazine moiety of pharmacological significance have been synthesized. All the synthesized compounds were screened for their in vitro antileishmanial and antioxidant activities. Compounds 5f (IC50=79.0µM) and 6f (IC50=79.0µM) were shown significant antileishmanial activity when compared with standard sodium stibogluconate (IC50=490.0µM). Compounds 5b (IC50=13.96µM) and 6b (IC50=13.96µM) showed significant antioxidant activity...
August 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28655656/lessons-learned-from-read-across-case-studies-for-repeated-dose-toxicity
#19
Terry W Schultz, Mark T D Cronin
A series of case studies designed to further acceptance of read-across predictions, especially for chronic health-related endpoints, have been evaluated with regard to the knowledge and insight they provide. A common aim of these case studies was to examine sources of uncertainty associated with read-across. While uncertainty is related to the quality and quantity of the read across endpoint data, uncertainty also includes a variety of other factors, the foremost of which is uncertainty associated with the justification of similarity and quantity and quality of data for the source chemical(s)...
June 24, 2017: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/28636542/niaoduqing-granules-relieve-chronic-kidney-disease-symptoms-by-decreasing-renal-fibrosis-and-anemia
#20
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...
June 14, 2017: Oncotarget
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