Targeting the JAK/STAT Pathway: A Combined Ligand- and Target-Based Approach

Gálvez-Llompart, María; Ocello, Riccardo; Rullo, Laura; Stamatakos, Serena; Alessandrini, Irene; Zanni, Riccardo; Tuñón, Iñaki; Cavalli, Andrea; Candeletti, Sanzio; Masetti, Matteo; Romualdi, Patrizia; Recanatini, Maurizio

doi:10.1021/acs.jcim.0c01468

Cited by 8 publications

(9 citation statements)

References 31 publications

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“…The name assigned by the ZINC database, the 2D structure, the similarity score, and the affinity towards JAK3 resulting from the docking process for the five most promising compounds not used in pharmacotherapies are shown in Table 6. In the scientific literature, the reported binding affinities of compounds targeting JAK3, as determined through in silico studies, range from −5.64 kcal/mol to −9.97 kcal/mol [39,41]. In the present analysis, the binding affinity of ZINC000072135158 towards JAK3 was determined to be −8.6 kcal/mol.…”

Section: Zinc000584884024mentioning

confidence: 67%

Novel Potential Janus Kinase Inhibitors with Therapeutic Prospects in Rheumatoid Arthritis Addressed by In Silico Studies

et al. 2023

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Rheumatoid arthritis (RA) is a debilitating autoimmune disorder with an inflammatory condition targeting the joints that affects millions of patients worldwide. Several unmet needs still need to be addressed despite recent improvements in the management of RA. Although current RA therapies can diminish inflammation and alleviate symptoms, many patients remain unresponsive or experience flare-ups of their ailment. The present study aims to address these unmet needs through in silico research, with a focus on the identification of novel, potentially active molecules. Therefore, a molecular docking analysis has been conducted using AutoDockTools 1.5.7 on Janus kinase (JAK) inhibitors that are either approved for RA or in advanced phases of research. The binding affinities of these small molecules against JAK1, JAK2, and JAK3, which are target proteins implicated in the pathophysiology of RA, have been assessed. Subsequent to identifying the ligands with the highest affinity for these target proteins, a ligand-based virtual screening was performed utilizing SwissSimilarity, starting with the chemical structures of the previously identified small molecules. ZINC252492504 had the highest binding affinity (−9.0 kcal/mol) for JAK1, followed by ZINC72147089 (−8.6 kcal/mol) for JAK2, and ZINC72135158 (−8.6 kcal/mol) for JAK3. Using SwissADME, an in silico pharmacokinetic evaluation showed that oral administration of the three small molecules may be feasible. Based on the preliminary results of the present study, additional extensive research is required for the most promising candidates to be conducted so their efficacy and safety profiles can be thoroughly characterized, and they can become medium- and long-term pharmacotherapeutic solutions for the treatment of RA.

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Section: Zinc000584884024mentioning

confidence: 67%

Novel Potential Janus Kinase Inhibitors with Therapeutic Prospects in Rheumatoid Arthritis Addressed by In Silico Studies

et al. 2023

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“…CEP-33779 was used as a positive inhibitor of JAK2. Each point was assayed in duplicate (N = 2) and is expressed as the mean ± SD ( 28 ).…”

Section: Methodsmentioning

confidence: 99%

Regulation of microglia related neuroinflammation contributes to the protective effect of Gelsevirine on ischemic stroke

Xing

Zhu

et al. 2023

Front. Immunol.

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Stroke, especially ischemic stroke, is an important cause of neurological morbidity and mortality worldwide. Growing evidence suggests that the immune system plays an intricate function in the pathophysiology of stroke. Gelsevirine (Gs), an alkaloid from Gelsemium elegans, has been proven to decrease inflammation and neuralgia in osteoarthritis previously, but its role in stroke is unknown. In this study, the middle cerebral artery occlusion (MCAO) mice model was used to evaluate the protective effect of Gs on stroke, and the administration of Gs significantly improved infarct volume, Bederson score, neurobiological function, apoptosis of neurons, and inflammation state in vivo. According to the data in vivo and the conditioned medium (CM) stimulated model in vitro, the beneficial effect of Gs came from the downregulation of the over-activity of microglia, such as the generation of inflammatory factors, dysfunction of mitochondria, production of ROS and so on. By RNA-seq analysis and Western-blot analysis, the JAK-STAT signal pathway plays a critical role in the anti-inflammatory effect of Gs. According to the results of molecular docking, inhibition assay, and thermal shift assay, the binding of Gs on JAK2 inhibited the activity of JAK2 which inhibited the over-activity of JAK2 and downregulated the phosphorylation of STAT3. Over-expression of a gain-of-function STAT3 mutation (K392R) abolished the beneficial effects of Gs. So, the downregulation of JAK2-STAT3 signaling pathway by Gs contributed to its anti-inflammatory effect on microglia in stroke. Our study revealed that Gs was benefit to stroke treatment by decreasing neuroinflammation in stroke as a potential drug candidate regulating the JAK2-STAT3 signal pathway.

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“…As α‐amylase is an important target for the treatment of diabetes mellitus and the development of new drugs, scientists are showing great interest in this enzyme 4 . In this regard, 3D computer‐aided drug design methods, such as molecular docking and molecular dynamics (MD), take into account ligand‐receptor simulation systems 5 . Molecular docking analysis models the interaction between a molecule and a protein at the atomic level.…”

Section: Introductionmentioning

confidence: 99%

Drug screening of α‐amylase inhibitors as candidates for treating diabetes

Alp

Misturini

Sastre

et al. 2023

J Cellular Molecular Medi

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In the present study, the identification of potential α‐amylase inhibitors is explored as a potential strategy for treating type‐2 diabetes mellitus. A computationally driven approach using molecular docking was employed to search for new α‐amylase inhibitors. The interactions of potential drugs with the enzyme's active site were investigated and compared with the contacts established by acarbose (a reference drug for α‐amylase inhibition) in the crystallographic structure 1B2Y. For this active site characterization, both molecular docking and molecular dynamics simulations were performed, and the residues involved in the α‐amylase–acarbose complex were considered to analyse the potential drug's interaction with the enzyme. Two potential α‐amylase inhibitors (AN‐153I105594 and AN‐153I104845) have been selected following this computational strategy. Both compounds established a large number of interactions with key binding site α‐amylase amino acids and obtained a comparable docking score concerning the reference drug (acarbose). Aiming to further analyse candidates' properties, their ADME (absorption, distribution, metabolism, excretion) parameters, druglikeness, organ toxicity, toxicological endpoints and median lethal dose (LD50) were estimated. Overall estimations are promising for both candidates, and in silico toxicity predictions suggest that a low toxicity should be expected.

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Targeting the JAK/STAT Pathway: A Combined Ligand- and Target-Based Approach

Cited by 8 publications

References 31 publications

Novel Potential Janus Kinase Inhibitors with Therapeutic Prospects in Rheumatoid Arthritis Addressed by In Silico Studies

Novel Potential Janus Kinase Inhibitors with Therapeutic Prospects in Rheumatoid Arthritis Addressed by In Silico Studies

Regulation of microglia related neuroinflammation contributes to the protective effect of Gelsevirine on ischemic stroke

Drug screening of α‐amylase inhibitors as candidates for treating diabetes

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