2022
DOI: 10.1021/acsomega.1c06715
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Unraveling the Molecular Mechanism of Recognition of Selected Next-Generation Antirheumatoid Arthritis Inhibitors by Janus Kinase 1

Abstract: Rheumatoid arthritis (RA) is a chronic immune-related condition, primarily of joints, and is highly disabling and painful. The inhibition of Janus kinase (JAK)-related cytokine signaling pathways using small molecules is prevalent nowadays. The JAK family belongs to nonreceptor cytoplasmic protein tyrosine kinases (PTKs), including JAK1, JAK2, JAK3, and TYK2 (tyrosine kinase 2). JAK1 has received significant attention after being identified as a promising target for developing anti-RA therapeutics. Currently, … Show more

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Cited by 14 publications
(9 citation statements)
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“…Next, there are seven targets related to metabolic diseases, such as 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and cannabinoid receptor 1 (CB1R), which are considered as attractive targets for the treatment of obesity and related metabolic diseases. Finally, there are 11 targets related to inflammatory immune diseases, such as Janus kinases (JAK1–JAK3), the popular targets for rheumatoid arthritis (RA) research, and two important target genes in the development of osteoarthritis (OA): MMP-3 and MMP-13. , Detailed descriptions of these 56 targets can be found in the Supporting Information, and details of the structure–activity data sets of small-molecule inhibitors of 56 disease-related targets are in Table S1, in which there are 24 targets with inhibitors over 10 000 and 16 targets with inhibitors between 5000 and 10 000; this indicates that the vast majority of targets are supported by sufficient structure–activity data about their inhibitors.…”
Section: Resultsmentioning
confidence: 99%
“…Next, there are seven targets related to metabolic diseases, such as 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and cannabinoid receptor 1 (CB1R), which are considered as attractive targets for the treatment of obesity and related metabolic diseases. Finally, there are 11 targets related to inflammatory immune diseases, such as Janus kinases (JAK1–JAK3), the popular targets for rheumatoid arthritis (RA) research, and two important target genes in the development of osteoarthritis (OA): MMP-3 and MMP-13. , Detailed descriptions of these 56 targets can be found in the Supporting Information, and details of the structure–activity data sets of small-molecule inhibitors of 56 disease-related targets are in Table S1, in which there are 24 targets with inhibitors over 10 000 and 16 targets with inhibitors between 5000 and 10 000; this indicates that the vast majority of targets are supported by sufficient structure–activity data about their inhibitors.…”
Section: Resultsmentioning
confidence: 99%
“…The binding free energy of JAK1/SOCS1 was calculated using the widely used MM/PBSA scheme ,, utilizing the MMPBSA.py script of the AMBER18 package. The binding free energy (Δ G bind ) is composed of three crucial factors, namely, internal energy (Δ E internal ), desolvation free energy (Δ G solv ), and configurational entropy ( T Δ S ), which can be correlated using the following equations where Δ E internal is further composed of Δ E covalent (bond, dihedral, and angle), Δ E elec (electrostatic), and Δ E vdW (van der Waals) terms.…”
Section: Methodsmentioning
confidence: 99%
“…64 MM/PBSA Calculations. The binding free energy of JAK1/SOCS1 was calculated using the widely used MM/ PBSA scheme [27][28][29]65,66 utilizing the MMPBSA.py script of the AMBER18 package. The binding free energy (ΔG bind ) is composed of three crucial factors, namely, internal energy (ΔE internal ), desolvation free energy (ΔG solv ), and configurational entropy (TΔS), which can be correlated using the following equations…”
Section: ■ Introductionmentioning
confidence: 99%
“…Protein structure network (PSN) approaches were used to study the allostery effect on network connectivity that depicts communications at a larger distance. The PSN represents a structural network comprising nodes and edges. Here, the C α atom of amino acid residues represents a node, and edges show interactions among nodes with a cutoff distance of 7 Å between two C α atoms.…”
Section: Methodsmentioning
confidence: 99%