Structural Analysis of Janus Tyrosine Kinase Variants in Hematological Malignancies: Implications for Drug Development and Opportunities for Novel Therapeutic Strategies

Rodriguez Moncivais, Omar J.; Chavez, Stephanie A.; Estrada Jimenez, Victor H.; Sun, Shengjie; Li, Lin; Kirken, Robert A.; Rodriguez, Georgialina

doi:10.3390/ijms241914573

Cited by 4 publications

(2 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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%

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.

View full text Add to dashboard Cite

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.

show abstract

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.

View full text Add to dashboard Cite

show abstract

“…The Prime commercial program does not have this limitation. Both software products have been successfully used to construct three-dimensional homologous models of proteins or parts thereof [25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Development of A. solani β-tubulin models and comparison of docking results for benzo[d]azoles derivatives as potential antifungal agents

Obydennov,

Kalinina,

Glukhareva

et al. 2024

Chim.Tech.Acta

View full text Add to dashboard Cite

An approach to developing a docking protocol using free software such as KNIME, DataWarrior, AutoDock Vina, AutoDockTools, OpenBabel and the SWISS-MODEL service was described. In particular, the process of generating possible isomeric structures using KNIME chemoinformatics libraries is described. A library of benzo[d]azoles containing 145 compounds with homologous models of Alternaria solani β-tubulin obtained in two ways: using the commercial Prime program and the free SWISS-MODEL service, the comparison of results was shown. Despite the less preorganization of the binding cavity of the homologous model obtained using SWISS-MODEL, the correlation of the results between the two methods were observed. The correlation coefficients were as follows: Pearson was 0.65, Spearman was 0.62. According to the docking results, 99% of the studied 2-aminobenzo[d]azoles derivatives showed a docking score of no more than –7, which indicates that these compounds are promising for studying the fungicidal activity, in particular against A. solani. Without taking into account pharmacokinetic characteristics, benzo[d]imidazole derivatives containing a sulfanilamidine substituent at the 2-amino group and thioacetyl derivatives of 2-aminobenzo[d]imidazole are of particular interest in the search for new antitubulin fungicides.

show abstract

A novel approach to study multi-domain motions in JAK1’s activation mechanism based on energy landscape

Sun,

Rodriguez,

Zhao

et al. 2024

Briefings in Bioinformatics

Self Cite

View full text Add to dashboard Cite

The family of Janus Kinases (JAKs) associated with the JAK–signal transducers and activators of transcription signaling pathway plays a vital role in the regulation of various cellular processes. The conformational change of JAKs is the fundamental steps for activation, affecting multiple intracellular signaling pathways. However, the transitional process from inactive to active kinase is still a mystery. This study is aimed at investigating the electrostatic properties and transitional states of JAK1 to a fully activation to a catalytically active enzyme. To achieve this goal, structures of the inhibited/activated full-length JAK1 were modelled and the energies of JAK1 with Tyrosine Kinase (TK) domain at different positions were calculated, and Dijkstra’s method was applied to find the energetically smoothest path. Through a comparison of the energetically smoothest paths of kinase inactivating P733L and S703I mutations, an evaluation of the reasons why these mutations lead to negative or positive regulation of JAK1 are provided. Our energy analysis suggests that activation of JAK1 is thermodynamically spontaneous, with the inhibition resulting from an energy barrier at the initial steps of activation, specifically the release of the TK domain from the inhibited Four-point-one, Ezrin, Radixin, Moesin-PK cavity. Overall, this work provides insights into the potential pathway for TK translocation and the activation mechanism of JAK1.

show abstract

Structural Analysis of Janus Tyrosine Kinase Variants in Hematological Malignancies: Implications for Drug Development and Opportunities for Novel Therapeutic Strategies

Cited by 4 publications

References 64 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

Development of A. solani β-tubulin models and comparison of docking results for benzo[d]azoles derivatives as potential antifungal agents

A novel approach to study multi-domain motions in JAK1’s activation mechanism based on energy landscape

Contact Info

Product

Resources

About