An overview of small-molecule agents for the treatment of psoriasis

Bioorganic & Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 119, P. 118067 - 118067

Published: Jan. 15, 2025

Language: Английский

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Revealing innovative JAK1 and JAK3 inhibitors: a comprehensive study utilizing QSAR, 3D-Pharmacophore screening, molecular docking, molecular dynamics, and MM/GBSA analyses

Frontiers in Molecular Biosciences, Journal Year: 2024, Volume and Issue: 11

Published: March 7, 2024

The heterocycle compounds, with their diverse functionalities, are particularly effective in inhibiting Janus kinases (JAKs). Therefore, it is crucial to identify the correlation between complex structures and biological activities for development of new drugs treatment rheumatoid arthritis (RA) cancer. In this study, a set 28 heterocyclic compounds selective JAK1 JAK3 was employed construct quantitative structure-activity relationship (QSAR) models using multiple linear regression (MLR). Artificial neural network (ANN) were QSAR models. robustness stability assessed through internal external methodologies, including domain applicability (DoA). molecular descriptors incorporated into model exhibited satisfactory receptor-ligand JAKs observed X-ray crystallography, making interpretable predictive. Furthermore, pharmacophore ADRRR ADHRR designed each JAK3, proving discriminating active decoys. Both demonstrated good performance identifying an ROC 0.83 0.75 model. Using model, most promising selected based on strong affinity compared studied series JAK3. Notably, pharmacokinetic, physicochemical properties, (As ZINC79189223 ZINC66252348) found be consistent therapeutic effects RA, owing non-toxic, cholinergic nature, absence P-glycoprotein, high gastrointestinal absorption, ability penetrate blood-brain barrier. ADMET properties assessed, dynamics MM/GBSA analysis revealed these molecules.

Language: Английский

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Computational insights of deucravacitinib’s selectivity for TYK2 pseudokinase vs. JAK kinase domain via molecular modeling studies

Journal of Biomolecular Structure and Dynamics, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 15

Published: April 9, 2025

Deucravacitinib (Sotyktu) stands out as a novel and highly specific oral inhibitor targeting tyrosine kinase 2 (TYK2). Its mechanism of action involves an allosteric binding, to catalytically inactive pseudokinase domain TYK2, this stabilizes inhibitory contact between the catalytic regulatory domains. This inhibition Janus (JAK) is associated with suppression cytokine signaling using diverse molecules defining wide importance in current research. In our recent investigation, we examined selectivity TYK2JH2 inhibitor, deucravacitinib, against four JAK kinases (JAK1, JAK2, JAK3, TYK2) TYK2 pseudokinases utilizing merged approach involving molecular docking, dynamics analysis (300 ns), binding free energy calculation through mechanics Poisson - Boltzmann surface area (MM-PBSA) scheme. The results obtained indicate that deucravacitinib effectively interacts ATP-binding site hydrogen bond formation, electrostatic attraction, notably, van der Waals interaction. We found calculated affinity demonstrates reduction TYK2JH2-deucravacitinib complex due increased favorable intermolecular contribution. Consequently, exhibits greater for compared other JAKs. Moreover, interaction DPG motif residues hinge region contributed stabilization robustly formed bonds. hydrophobic caused adopt closed conformation, thereby minimizing protein movement at glycine loop protein. summary, study holds significant potential informing strategic design inhibitors enhanced affinity.

Language: Английский

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Pharmacophore Modeling of Janus Kinase Inhibitors: Tools for Drug Discovery and Exposition Prediction

Molecules, Journal Year: 2025, Volume and Issue: 30(10), P. 2183 - 2183

Published: May 16, 2025

Pesticides are essential in agriculture for protecting crops and boosting productivity, but their widespread use may pose significant health risks. Farmworkers face direct exposure through skin contact inhalation, which lead to hormonal imbalances, neurological disorders, elevated cancer Moreover, pesticide residues food water affect surrounding communities. One of the lesser investigated issues is immunotoxicity, mostly because chronic effects compound very complex study. As a case study, this work utilized pharmacophore modeling virtual screening identify pesticides that inhibit Janus kinases (JAK1, JAK2, JAK3) tyrosine kinase 2 (TYK2), pivotal immune response regulation, associated with development increased infection susceptibility. We identified 64 potential candidates, 22 have previously been detected human body, as confirmed by Human Metabolome Database. These results underscore critical need further research into immunotoxic impacts respective on health.

Language: Английский

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Computational insights into rational design and virtual screening of pyrazolopyrimidine derivatives targeting Janus kinase 3 (JAK3)

Frontiers in Chemistry, Journal Year: 2024, Volume and Issue: 12

Published: Aug. 12, 2024

The Janus kinase 3 (JAK3) family, particularly JAK3, is pivotal in initiating autoimmune diseases such as rheumatoid arthritis. Recent advancements have focused on developing antirheumatic drugs targeting leading to the discovery of novel pyrazolopyrimidine-based compounds potential inhibitors. This research employed covalent docking, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) analysis, molecular dynamics modeling, and MM/GBSA (Molecular Mechanics Generalized Born Surface Area) binding free energy techniques screen 41 silico-designed pyrazolopyrimidine derivatives. Initially, 3D structures JAK3 enzyme were generated using SWISS-MODEL, followed by virtual screening docking via AutoDock4 (AD4). selection process involved AMES test, affinity assessment, narrowing down candidates 27 that passed toxicity test. Further identified 21 most promising due their high favourable profiles. Subsequent development led creation nine potent molecules, with derivatives 43 46 showing exceptional upon evaluation through simulation calculations over 300 nanoseconds, comparable tofacitinib, an approved RA drug. However, L21 L46 demonstrated stable performance, suggesting effectiveness treating arthritis other conditions associated inhibition.

Language: Английский

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Molecular basis of JAK kinase regulation guiding therapeutic approaches: Evaluating the JAK3 pseudokinase domain as a drug target

Advances in Biological Regulation, Journal Year: 2024, Volume and Issue: unknown, P. 101072 - 101072

Published: Dec. 1, 2024

Language: Английский

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Revisiting Structure-activity Relationships: Unleashing the potential of selective Janus kinase 1 inhibitors

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 149, P. 107506 - 107506

Published: May 29, 2024

Language: Английский

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