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ADME in silico

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https://www.readbyqxmd.com/read/27903217/rational-drug-discovery-of-hcv-helicase-inhibitor-improved-docking-accuracy-with-multiple-seedings-of-autodock-vina-and-in-situ-minimization
#1
SeeKhai Lim, Rozana Othman, Rohana Yusof, ChoonHan Heh
BACKGROUND: Hepatitis C is a significant cause for end-stage liver diseases and liver transplantation which affects approximate 3% of the global populations. Despite the present of several direct antiviral agents in the treatment of hepatitis C, the standard treatment for HCV is accompanied by several drawbacks such as adverse side effects, high pricing of medications and the rapid emerging rate of resistant HCV variants. OBJECTIVES: To discover potential inhibitors for HCV helicase through an optimized in silico approach...
November 30, 2016: Current Computer-aided Drug Design
https://www.readbyqxmd.com/read/27773722/prediction-of-pharmacokinetic-and-toxicological-parameters-of-a-4-phenylcoumarin-isolated-from-geopropolis-in-silico-and-in-vitro-approaches
#2
Marcos Guilherme da Cunha, Gilson César Nobre Franco, Marcelo Franchin, John A Beutler, Severino Matias de Alencar, Masaharu Ikegaki, Pedro Luiz Rosalen
In silico and in vitro methodologies have been used as important tools in the drug discovery process, including from natural sources. The aim of this study was to predict pharmacokinetic and toxicity (ADME/Tox) properties of a coumarin isolated from geopropolis using in silico and in vitro approaches. Cinnamoyloxy-mammeisin (CNM) isolated from Brazilian M. scutellaris geopropolis was evaluated for its pharmacokinetic parameters by in silico models (ACD/Percepta™ and MetaDrug™ software). Genotoxicity was assessed by in vitro DNA damage signaling PCR array...
October 20, 2016: Toxicology Letters
https://www.readbyqxmd.com/read/27744115/design-synthesis-cytotoxicity-hutopoii%C3%AE-inhibitory-activity-and-molecular-docking-studies-of-pyrazole-derivatives-as-potential-anticancer-agents
#3
Raquib Alam, Divya Wahi, Raja Singh, Devapriya Sinha, Vibha Tandon, Abhinav Grover, Rahisuddin
In an attempt to find potential anticancer agents, a series of novel ethyl 4-(3-(aryl)-1-phenyl-1H-pyrazol-4-yl)-2-oxo-6-(pyridin-3-yl)cyclohex-3-enecarboxylates 5a-i and 5-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(pyridin-3-yl)-4,5-dihydropyrazole-1-carbothioamides 6a-i were designed, synthesized and evaluated for their topoisomerase IIα inhibitory activity and in vitro cytotoxicity against a panel of cancerous cell lines (MCF-7, NCI-H460, HeLa) and a normal cell line (HEK-293T). Molecular docking studies of all the synthesized compounds into the binding site of topoisomerase IIα protein (PDB ID: 1ZXM) were performed to gain a comprehensive understanding into plausible binding modes...
October 5, 2016: Bioorganic Chemistry
https://www.readbyqxmd.com/read/27607834/pharmacophore-modeling-3d-qsar-and-in-silico-adme-prediction-of-n-pyridyl-and-pyrimidine-benzamides-as-potent-antiepileptic-agents
#4
Ruchi Malik, Pakhuri Mehta, Shubham Srivastava, Bhanwar Singh Choudhary, Manish Sharma
Biological mechanism attributing mutations in KCNQ2/Q3 results in benign familial neonatal epilepsy (BFNE), a rare form of epilepsy and thus neglected. It offers a potential target for antiepileptic drug discovery. In the present work, a pharmacophore-based 3D-QSAR model was generated for a series of N-pyridyl and pyrimidine benzamides possessing KCNQ2/Q3 opening activity. The pharmacophore model generated contains one hydrogen bond donor (D), one hydrophobic (H), and two aromatic rings (R). They are the crucial molecular write-up detailing predicted binding efficacy of high affinity and low affinity ligands for KCNQ2/Q3 opening activity...
September 8, 2016: Journal of Receptor and Signal Transduction Research
https://www.readbyqxmd.com/read/27539315/design-and-green-synthesis-of-thieno-2-3-d-pyrimidine-analogues-as-potential-antiproliferative-agents
#5
Rupinder Kaur Gill, Virender Kumar, Mahendra Bishnoi, Kamalendra Yadav, Kanthi Kiran Kondepudi, Jitender Bariwal
4-Substituted thieno[2,3-d]pyrimidines have been synthesized via microwave-assisted methods and screened for their cytotoxic activity against liver HepG-2, lung NCI-H522, melanoma A-375, pancreatic MIA PaCa-2 and colon CaCo-2 human cancer cell lines using MTT assay. The antiproliferative potential of most active compounds 20b and 20f (piperidino substituted); and 22d (hybrid analogue of Dasatinib) was further assessed and confirmed by calcein AM and colony formation assay, which revealed the higher potency of hybrid analogue 22d in comparison to piperidino substituted derivative 20f...
August 17, 2016: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/27528517/microwave-assisted-synthesis-of-pyrimidines-in-ionic-liquid-and-their-potency-as-non-classical-malarial-antifolates
#6
Jaimin D Bhatt, Chaitanya J Chudasama, Kanuprasad D Patel
Synthesis of pyrazole-linked triazolo-pyrimidine hybrids was achieved by employing Biginelli-type reaction methodology in an ionic liquid (triethylammonium acetate) under microwave irradiation. This method proved to be highly efficient and the ionic liquid employed was found recyclable for up to five consecutive cycles. The synthesized molecules were further screened for their antimalarial efficacy screening out the active scaffolds J15, J18, J21, J24, J27, and J30. The active molecules were evaluated in an enzyme inhibition study against the active Plasmodium falciparum dihydrofolate reductase (Pf-DHFR), computationally as well as in vitro, demonstrating their potency as DHFR inhibitors...
October 2016: Archiv der Pharmazie
https://www.readbyqxmd.com/read/27515040/discovery-of-camptothecin-based-topoisomerase-i-inhibitors-identification-using-an-atom-based-3d-qsar-pharmacophore-modeling-virtual-screening-and-molecular-docking-approach
#7
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
https://www.readbyqxmd.com/read/27429875/in-silico-screening-for-identification-of-novel-%C3%AE-1-3-glucan-synthase-inhibitors-using-pharmacophore-and-3d-qsar-methodologies
#8
Potshangbam Angamba Meetei, R S Rathore, N Prakash Prabhu, Vaibhav Vindal
The enzyme β-1,3-glucan synthase, which catalyzes the synthesis of β-1,3-glucan, an essential and unique structural component of the fungal cell wall, has been considered as a promising target for the development of less toxic anti-fungal agents. In this study, a robust pharmacophore model was developed and structure activity relationship analysis of 42 pyridazinone derivatives as β-1,3-glucan synthase inhibitors were carried out. A five-point pharmacophore model, consisting of two aromatic rings (R) and three hydrogen bond acceptors (A) was generated...
2016: SpringerPlus
https://www.readbyqxmd.com/read/27429110/identification-of-novel-small-molecules-that-bind-to-the-loop2-region-of-sclerostin-an-in-silico-computational-analysis
#9
K Muthusamy, M Subburaman, S Nagamani, C Kesavan
The goal of this study was to identify small molecular weight compounds that bind to sclerostin using in-silico methods because of the established importance of sclerostin-based therapies for the treatment of disease characterized by low bone mass. The zinc database (Zdb) revealed that nine potential molecules bind to the loop2 region (functional site) of sclerostin with ADME/T properties that are within an acceptable range defined for human use. Compounds 30160056 and 56871042 showed the highest docking score...
July 15, 2016: Physiological Research
https://www.readbyqxmd.com/read/27423261/retention-data-of-bile-acids-and-their-oxo-derivatives-in-characterization-of-pharmacokinetic-properties-and-in-silico-adme-modeling
#10
Jovana Trifunović, Vladan Borčić, Saša Vukmirović, Svetlana Goločorbin Kon, Momir Mikov
PURPOSE: Information on ADME properties of examined bile acids and their oxo derivatives are scarce, although the interest for bile acids and their use in nanochemistry and macromolecular chemistry is increasing. The purpose of this research was to evaluate the lipophilicity, a crucial physicochemical parameter for describing ADME properties of selected bile acids and their oxo derivatives, and to compare two approaches: experimentally determined hydrophobicity parameters and calculated logP values...
September 20, 2016: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/27278908/evaluation-of-the-gastroplus%C3%A2-advanced-compartmental-and-transit-acat-model-in-early-discovery
#11
N Gobeau, R Stringer, S De Buck, T Tuntland, B Faller
PURPOSE: The aim of this study was to evaluate the oral exposure predictions obtained early in drug discovery with a generic GastroPlus Advanced Compartmental And Transit (ACAT) model based on the in vivo intravenous blood concentration-time profile, in silico properties (lipophilicity, pKa) and in vitro high-throughput absorption-distribution-metabolism-excretion (ADME) data (as determined by PAMPA, solubility, liver microsomal stability assays). METHODS: The model was applied to a total of 623 discovery molecules and their oral exposure was predicted in rats and/or dogs...
September 2016: Pharmaceutical Research
https://www.readbyqxmd.com/read/27269198/bacterial-peptide-deformylase-inhibition-of-cyano-substituted-biaryl-analogs-synthesis-in-vitro-biological-evaluation-molecular-docking-study-and-in-silico-adme-prediction
#12
Firoz A Kalam Khan, Rajendra H Patil, Devanand B Shinde, Jaiprakash N Sangshetti
Herein, we report the synthesis and screening of cyano substituted biaryl analogs 5(a-m) as Peptide deformylase (PDF) enzyme inhibitors. The compounds 5a (IC50 value=13.16μM), 5d (IC50 value=15.66μM) and 5j (IC50 value=19.16μM) had shown good PDF inhibition activity. The compounds 5a (MIC range=11.00-15.83μg/mL), 5b (MIC range=23.75-28.50μg/mL) and 5j (MIC range=7.66-16.91μg/mL) had also shown potent antibacterial activity when compared with ciprofloxacin (MIC range=25-50μg/mL). Thus, the active derivatives were not only potent PDF inhibitors but also efficient antibacterial agents...
August 15, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27231830/identification-of-novel-acetylcholinesterase-inhibitors-indolopyrazoline-derivatives-and-molecular-docking-studies
#13
Sridevi Chigurupati, Manikandan Selvaraj, Vasudevan Mani, Kesavanarayanan Krishnan Selvarajan, Jahidul Islam Mohammad, Balaji Kaveti, Hriday Bera, Vasanth Raj Palanimuthu, Lay Kek Teh, Mohd Zaki Salleh
The synthesis of novel indolopyrazoline derivatives (P1-P4 and Q1-Q4) has been characterized and evaluated as potential anti-Alzheimer agents through in vitro Acetylcholinesterase (AChE) inhibition and radical scavenging activity (antioxidant) studies. Specifically, Q3 shows AChE inhibition (IC50: 0.68±0.13μM) with strong DPPH and ABTS radical scavenging activity (IC50: 13.77±0.25μM and IC50: 12.59±0.21μM), respectively. While P3 exhibited as the second most potent compound with AChE inhibition (IC50: 0...
August 2016: Bioorganic Chemistry
https://www.readbyqxmd.com/read/27216235/exploring-anti-inflammatory-potential-of-thiazolidinone-derivatives-of-benzenesulfonamide-via-synthesis-molecular-docking-and-biological-evaluation
#14
Sanjay B Bari, Sandip D Firake
BACKGROUND: The present study reports the synthesis and biological evaluation of thiazolidinone derivatives bearing benzenesulfonamide investigated for cyclooxygenase-2 (COX-2) inhibitory activity and in vivo anti-inflammatory activity. METHODS: The synthesis of 4-(4-oxo-2-substituted-1,3-thiazolidin-3-yl) benzenesulfonamide derivatives were carried out by conventional synthesis, involves the one-pot condensation reaction of sulfanilamide. The synthesized compounds were evaluated against COX-1 and human recombinant COX-2 by using colorimetric enzyme assay kit and in-vivo study was carried out by carageenan induced rat paw edema method...
May 24, 2016: Anti-inflammatory & Anti-allergy Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/27157006/development-of-cyanopyridine-triazine-hybrids-as-lead-multitarget-anti-alzheimer-agents
#15
Mudasir Maqbool, Apra Manral, Ehtesham Jameel, Jitendra Kumar, Vikas Saini, Ashutosh Shandilya, Manisha Tiwari, Nasimul Hoda, B Jayaram
A series of new cyanopyridine-triazine hybrids were designed, synthesized and screened as multitargeted anti-Alzheimer's agents. These molecules were designed while using computational techniques and were synthesized via a feasible concurrent synthetic route. Inhibition potencies of synthetic compounds 4a-4h against cholinesterases, Aβ1-42 disaggregation, oxidative stress, cytotoxicity, and neuroprotection against Aβ1-42-induced toxicity of the synthesized compounds were evaluated. Compounds 4d and 4h showed promising inhibitory activity on acetylcholinesterase (AChE) with IC50 values 0...
June 15, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27135466/exploration-of-a-library-of-3-4-methylenedioxy-aniline-derived-semicarbazones-as-dual-inhibitors-of-monoamine-oxidase-and-acetylcholinesterase-design-synthesis-and-evaluation
#16
Rati K P Tripathi, Gopal K Rai, Senthil R Ayyannan
A library of 3,4-(methylenedioxy)aniline-derived semicarbazones was designed, synthesized, and evaluated as monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibitors for the treatment of neurodegenerative diseases. Most of the new compounds selectively inhibited MAO-B and AChE, with IC50 values in the micro- or nanomolar ranges. Compound 16, 1-(2,6-dichlorobenzylidene)-4-(benzo[1,3]dioxol-5-yl)semicarbazide presented a balanced multifunctional profile of MAO-A (IC50 =4.52±0.032 μm), MAO-B (IC50 =0...
June 6, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27031173/multistep-reaction-based-de-novo-drug-design-generating-synthetically-feasible-design-ideas
#17
Brian B Masek, David S Baker, Roman J Dorfman, Karen DuBrucq, Victoria C Francis, Stephan Nagy, Bree L Richey, Farhad Soltanshahi
We describe a "multistep reaction driven" evolutionary algorithm approach to de novo molecular design. Structures generated by the approach include a proposed synthesis path intended to aid the chemist in assessing the synthetic feasibility of the ideas that are generated. The methodology is independent of how the design ideas are scored, allowing multicriteria drug design to address multiple issues including activity at one or more pharmacological targets, selectivity, physical and ADME properties, and off target liabilities; the methods are compatible with common computer-aided drug discovery "scoring" methodologies such as 2D- and 3D-ligand similarity, docking, desirability functions based on physiochemical properties, and/or predictions from 2D/3D QSAR or machine learning models and combinations thereof to be used to guide design...
April 25, 2016: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/27025921/flavanoids-as-potential-nedd-4-inhibitors-in-silico-discovery-using-molecular-docking-and-adme-studies
#18
Kamal Kumar Chaudhary, Sarvesh Kumar Gupta, Nidhi Mishra
NEDD-4 are closely related E3 ubiquitin-protein ligases that include a C2 domain, three or four WW domains and a catalytic HECT ubiquitin ligase domain. The WW domains of NEDD-4 proteins recognize substrates for ubiquitination by binding the sequence L/PPxY (the PY-motif) present in target proteins. NEDD-4 functions as a suppressor of the epithelial Na+ channel (ENaC), which interacts with NEDD-4 WW domains via PY-motifs located at its C-terminus. Fifty compounds, all of them flavanoids, were subjected to molecular docking studies...
March 30, 2016: Interdisciplinary Sciences, Computational Life Sciences
https://www.readbyqxmd.com/read/27013793/in-silico-screening-of-antibacterial-compounds-from-herbal-sources-against-vibrio-cholerae
#19
Sabah Perveen, Hotam Singh Chaudhary
BACKGROUND: The prolonged use of antibiotic viz., tetracycline, quinolones, ampicillin, etc., to reduce the infection of cholera, may failed due to the emergence of new Vibrio cholerae antibiotics resistant strains. Moreover, these antibiotics even restricted for patient suffering from severe dehydration. Hence, there is a call to find an alternative therapeutics against V. cholerae. The natures serve different herbs in its lap which might contain several natural therapeutic compounds almost all diseases...
October 2015: Pharmacognosy Magazine
https://www.readbyqxmd.com/read/26967552/docking-and-admet-prediction-of-few-gsk-3-inhibitors-divulges-6-bromoindirubin-3-oxime-as-a-potential-inhibitor
#20
Chaluveelaveedu Murleedharan Nisha, Ashwini Kumar, Archana Vimal, Bhukya Mounika Bai, Dharm Pal, Awanish Kumar
GSK-3 is a member of cellular kinases with diversified functions such as cellular differentiation, metabolic signaling, neuronal functions and apoptosis. It has been validated as an important therapeutic target in Alzheimer's disease and type 2 diabetes. Few molecules targeting GSK-3 are currently in clinical trials. In this study, we have compared certain docking and computational ADME (Absorption, Distribution, Metabolism, Excretion) parameters of a few GSK-3 targeted ligands (Indirubin, Hymenialdisine, Meridianins, 6-bromoindirubin-3-oxime) against two control molecules (Tideglusib and LY-2090314) to derive and analyze the basic drug-like properties of the test compounds...
April 2016: Journal of Molecular Graphics & Modelling
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