Progress on the Pharmacological Targeting of Janus Pseudokinases

Henry, Sean P.; Jorgensen, William

doi:10.1021/acs.jmedchem.3c00926

Cited by 3 publications

(2 citation statements)

References 142 publications

(493 reference statements)

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“…The JAKs uniquely possess an integrated pseudokinase domain (JH2) that regulates the adjacent kinase domain (JH1). The therapeutic targeting of JH2 domains has been less thoroughly explored and may present an avenue to modulate the JAKs without the adverse effects associated with targeting the adjacent JH1 domain ( Henry and Jorgensen, 2023 ; Rodriguez Moncivais et al, 2023 ). The potential of this strategy was recently demonstrated with the FDA approval of the TYK2 JH2 ligand deucravacitinib for treating plaque psoriasis.…”

Section: Introductionmentioning

confidence: 99%

“…The potential of this strategy was recently demonstrated with the FDA approval of the TYK2 JH2 ligand deucravacitinib for treating plaque psoriasis. In this light, the structure and targetability of the JAK pseudokinases are discussed, in conjunction with the state of development of ligands that bind to these domains ( Grant et al, 2023 ; Henry and Jorgensen, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

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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

Faris,

Cacciatore,

Alnajjar

et al. 2024

Front. Mol. Biosci.

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

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Faris,

Cacciatore,

Alnajjar

et al. 2024

Front. Mol. Biosci.

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

Shan,

Zhao,

Sun

et al. 2024

Bioorganic Chemistry

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

Faris,

Cacciatore,

Alnajjar

et al. 2024

Front. Chem.

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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 JAK3, leading to the discovery of novel pyrazolopyrimidine-based compounds as 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 to screen 41 in silico-designed pyrazolopyrimidine derivatives. Initially, 3D structures of the JAK3 enzyme were generated using SWISS-MODEL, followed by virtual screening and covalent docking via AutoDock4 (AD4). The selection process involved the AMES test, binding affinity assessment, and ADMET analysis, narrowing down the candidates to 27 compounds that passed the toxicity test. Further covalent docking identified compounds 21 and 41 as the most promising due to their high affinity and favourable ADMET profiles. Subsequent development led to the creation of nine potent molecules, with derivatives 43 and 46 showing exceptional affinity upon evaluation through molecular dynamics simulation and MM/GBSA calculations over 300 nanoseconds, comparable to tofacitinib, an approved RA drug. However, compounds L21 and L46 demonstrated stable performance, suggesting their effectiveness in treating rheumatoid arthritis and other autoimmune conditions associated with JAK3 inhibition.

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Progress on the Pharmacological Targeting of Janus Pseudokinases

Cited by 3 publications

References 142 publications

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

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

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

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

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