Novel Selective Orally Active CRTH2 Antagonists for Allergic Inflammation Developed from in Silico Derived Hits

2006 ◽  
Vol 49 (23) ◽  
pp. 6638-6641 ◽  
Author(s):  
Trond Ulven ◽  
Jean-Marie Receveur ◽  
Marie Grimstrup ◽  
Øystein Rist ◽  
Thomas M. Frimurer ◽  
...  
Keyword(s):  
In Silico ◽  
Allergic Inflammation ◽  
Orally Active

Discovery of an Orally Active and Long‐Acting DPP‐IV Inhibitor through Property‐Based Optimization with an in Silico Biotransformation Prediction Tool

ChemMedChem ◽  
2020 ◽  
Vol 15 (16) ◽  
pp. 1608-1617
Author(s):  
Shaogao Zeng ◽  
Wenyuan Dou ◽  
Manna Li ◽  
Yang Zhou ◽  
Jiehuang Guo ◽  
...  
Keyword(s):  
In Silico ◽  
Prediction Tool ◽  
Dpp Iv ◽  
Long Acting ◽  
Orally Active

Combining Hit Identification Strategies: Fragment-Based and in Silico Approaches to Orally Active 2-Aminothieno[2,3-d]pyrimidine Inhibitors of the Hsp90 Molecular Chaperone

2009 ◽  
Vol 52 (15) ◽  
pp. 4794-4809 ◽  
Author(s):  
Paul A. Brough ◽  
Xavier Barril ◽  
Jenifer Borgognoni ◽  
Patrick Chene ◽  
Nicholas G. M. Davies ◽  
...  
Keyword(s):  
Molecular Chaperone ◽  
In Silico ◽  
Hit Identification ◽  
Orally Active

scholarly journals Synthesis, In Vitro, In Vivo and In Silico Antidiabetic Bioassays of 4-Niztro(thio)phenoxyisobutyric Acids Acting as Unexpected PPARγ Modulators: An In Combo Study

2022 ◽  
Vol 15 (1) ◽  
pp. 102
Author(s):  
Blanca Colin-Lozano ◽  
Héctor Torres-Gomez ◽  
Sergio Hidalgo-Figueroa ◽  
Fabiola Chávez-Silva ◽  
Samuel Estrada-Soto ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Spectral Analysis ◽  
In Silico ◽  
In Vivo Studies ◽  
In Vitro Expression ◽  
Modes Of Action ◽  
In Vivo Effects ◽  
Orally Active

Four isobutyric acids (two nitro and two acetamido derivatives) were prepared in two steps and characterized using spectral analysis. The mRNA concentrations of PPARγ and GLUT-4 (two proteins documented as key diabetes targets) were increased by 3T3-L1 adipocytes treated with compounds 1–4, but an absence of in vitro expression of PPARα was observed. Docking and molecular dynamics studies revealed the plausible interaction between the synthesized compounds and PPARγ. In vivo studies established that compounds 1–4 have antihyperglycemic modes of action associated with insulin sensitization. Nitrocompound 2 was the most promising of the series, being orally active, and one of multiple modes of action could be selective PPARγ modulation due to its extra anchoring with Gln-286. In conclusion, we demonstrated that nitrocompound 2 showed strong in vitro and in vivo effects and can be considered as an experimental antidiabetic candidate.

Inhibitory Effect of the New Orally Active CCR4 Antagonist K327 on CCR4+CD4+ T Cell Migration into the Lung of Mice with Ovalbumin-Induced Lung Allergic Inflammation

Pharmacology ◽  
2009 ◽  
Vol 84 (3) ◽  
pp. 171-182 ◽  
Author(s):  
Takashi Sato ◽  
Masato Komai ◽  
Miho Iwase ◽  
Katsuya Kobayashi ◽  
Harunobu Tahara ◽  
...  
Keyword(s):  
Cell Migration ◽  
T Cell ◽  
Allergic Inflammation ◽  
Inhibitory Effect ◽  
Cd4 T Cell ◽  
T Cell Migration ◽  
Orally Active

In silico designing of novel inhibitors for triple inhibition of Aldose Reductase, Aldose Reductase like protein 1, and Aldehyde Reductase

2019 ◽  
Vol 15 ◽  
Author(s):  
Arpita Devi
Keyword(s):  
Aldose Reductase ◽  
Active Site ◽  
In Silico ◽  
Genetic Factors ◽  
Dynamics Simulation ◽  
Aqueous Environment ◽  
Aldehyde Reductase ◽  
Homologous Proteins ◽  
Different Types ◽  
Orally Active

: Cancer is a well-known and well-studied disease. There are environmental as well as genetic factors that trigger cancer. All forms of cancer are associated with deregulation of genes and proteins. Aldose reductase, Aldose Reductase like protein 1 and Aldehyde Reductase are homologous proteins which are overexpressed in different types of cancer. They are NADPH-dependent oxidoreductases. The active site is conserved, thus there is very less substrate specificity among those proteins. In this study, novel molecules targeting the three proteins are designed. Molecular docking is performed to study the binding affinity of each ligand towards the targets. The six molecules studied are found to have better in silico affinity than tolrestat (known inhibitor) The designed molecules are predicted to be orally active. Finally, Molecular Dynamics Simulation shows that the protein ligand complexes are stable in aqueous environment.

Structure-based virtual screening of natural compounds as potential anti-allergy agents against cytokine alarmins (TSLP and IL-33)

2021 ◽  
Vol 18 ◽  
Author(s):  
Rahma Muhammad Adamu ◽  
Rita Singh Majumdhar ◽  
Abdullahi Ibrahim Uba
Keyword(s):  
Virtual Screening ◽  
Natural Product ◽  
In Silico ◽  
Early Stage ◽  
Allergic Inflammation ◽  
Prediction Method ◽  
Allergic Diseases ◽  
Natural Compounds ◽  
Dynamics Simulation ◽  
Th2 Cells

Background: Allergic diseases are turning into an expanding occurrence around the globe, imposing a socioeconomic burden, causing grimness and even death. Allergen encounter initiates the influx of TH2 cells, triggering the production of TH2 associated cytokines (IL-4, IL-5, and IL-13), which in turn promotes the detrimental allergic inflammation associated with asthma, allergic rhinitis, food allergy, urticaria, atopic eczema, and anaphylaxis. Cytokine alarmins (TSLP and IL-33) produced by epithelial cells play important roles in the promotion of TH2 cell development and the initiation of allergic pathogenesis. Objectives: The objective of this study is to target cytokine alarmins (TSLP and IL-33) as novel therapeutic proteins using natural compounds as a potential cure at an early stage of allergic diseases. Methods: Structure-based virtual screening of two large natural compounds databases (Universal Natural product Database (UNPD) and ZINC natural product database) was conducted for identification of TSLP and IL-33 inhibitors using Autodock Vina followed by rescoring of the hit compounds using Autodock 4.2 software. In silico physicochemical, pharmacokinetic, and toxicity analyses were conducted to assess the drug-like properties of the hit compounds. The binding mode stability of UNPD116849, ZINC01448143, and ZINC04096134 in the binding pocket of TSLP and IL-33 was probed by all-atom 50 ns molecular dynamics simulation. Results: Five natural compounds (UNPD111, UNPD116849, ZINC01448143, ZINC15957528, and ZINC04096134) containing different structural moieties (steroidal, chromone, benzodioxole, and indole), were identified to inhibit TSLP and IL-33, with limonin (ZINC04096134) found to demonstrate dual inhibitory activity potential. These compounds were found to be drug-like and toxicity-free using in silico Absorption, Distribution, Metabolism, Elimination, and Toxicity (ADME-T) prediction method. Taken together, this study suggests the dual inhibition potential of limonin (ZINC04096134) against the cytokine alarmins. Conclusion: Five natural compounds with diverse structural moieties (steroidal, chromone, benzodioxole, and indole) were virtually identified as hits compounds against cytokine alarmins (TSLP and IL-33), with limonin showing dual inhibitory potential.

scholarly journals Designing, Cytotoxic Evaluation, Molecular Docking and in Silico Pharmacokinetic Prediction of New Hydrocortisone Derivatives as Anti-Asthmatics Drugs

2020 ◽  
Vol 10 (4) ◽  
pp. 8-16 ◽  
Author(s):  
Walid Bououden ◽  
Yacine Benguerba
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Similarity Search ◽  
Structural Similarity ◽  
Biological Properties ◽  
Cell Permeability ◽  
Toxicity Prediction ◽  
Web Based ◽  
Keywords Corticosteroids ◽  
Orally Active

A series of new 20 corticosteroids were subjected to molecular property prediction. The Molecular, Physicochemical, and Biological properties were determined using Molinspiration Cheminformatics software. These compounds were further subjected to Toxicity Predictions using the Osiris Software. The calculated drug-related properties of the designed molecules were similar to those found in most marketed drugs. Amongst the proposed molecules, fourteen promising candidates can be considered as promising structures for the synthesis of new and more effective anti-asthmatic drugs. Result indicates that the derivatives are orally active molecules.  In-silico ADME and toxicity prediction was accomplished with the help of Swiss-ADMET tool provides the latest and most inclusive for diverse chemicals associated with known Absorption, Distribution, Metabolism, Excretion and Toxicity profiles. furthermore, BBB (Blood brain barrier) penetration, HIA (Human intestinal absorption), Caco-2 cell permeability and Ames test were calculated using ADMET web-based query tools incorporating a molecular build in interface enable the database to be queried by Smiles and structural similarity search. According to molecular docking results, derivatives No 4, 10 and 11 showed better docking Scores values compared to other derivatives and also dexamethasone and hydrocortisone. Keywords: Corticosteroids, Drug-likeness, Lipophilicity, Anti-asthmatic, ADME.

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