title: Inhibition of Janus kinases by tyrosine phosphorylation inhibitor, Tyrphostin AG-490.
abstract: Janus kinases (JAKs) belong to a crucial family of tyrosine kinases, implicated in the patho-physiology of multiple cancer types, and serve as striking therapeutic targets. To date, many potent, either ATP-competitive (PTK domain) or non-ATP-competitive JAK inhibitors have been identified. Among them, Tyrphostin AG-490 (2-cyano-3-(3,4-dihydroxyphenyl)-N-(phenylmethyl)-2-propenamide) is a well-known ATP-competitive inhibitor. However, its mode of action, details of interacting residues, and induced conformational changes in JAK-specific binding sites remain elusive. Here, through comparative structure analysis, molecular docking, and molecular dynamics simulation assays, we explored comparative binding patterns of AG-490 against JAK1, JAK2, and JAK3. Our results entail noteworthy observations about the binding affinity of AG-490 by illustrating distinctive amino acid residues lying at the conserved ATP-binding domains of JAK family members. By subsequent assessment of their structural homology and conserved structural folds, we highlight intriguing prospects to design more specific and potent inhibitors for selective targeting of JAK family members. Our comparative study provides a platform for the rational design of precise and potent inhibitor for selective targeting of JAK family members.
authors.affiliation: a National Center for Bioinformatics , Quaid-i-Azam University , Islamabad , Pakistan.
authors.forename: Sajid
authors.initials: S
authors.lastname: Rashid
authors.affiliation: a National Center for Bioinformatics , Quaid-i-Azam University , Islamabad , Pakistan.
authors.forename: Nousheen
authors.initials: N
authors.lastname: Bibi
authors.affiliation: a National Center for Bioinformatics , Quaid-i-Azam University , Islamabad , Pakistan.
authors.forename: Zahida
authors.initials: Z
authors.lastname: Parveen
authors.affiliation: a National Center for Bioinformatics , Quaid-i-Azam University , Islamabad , Pakistan.
authors.forename: Shagufta
authors.initials: S
authors.lastname: Shafique
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D016415:Sequence Alignment; D020032:Tyrphostins / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D047428:Protein Kinase Inhibitors; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D000255:Adenosine Triphosphate; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D053612:Janus Kinases
keywords: AG-490; JAKs; PTK domain; molecular docking; molecular dynamics simulation