title: Discovery of Subtype Selective Janus Kinase (JAK) Inhibitors by Structure-Based Virtual Screening.
abstract: Janus kinase inhibitors represent a promising opportunity for the pharmaceutical intervention of various inflammatory and oncological indications. Subtype selective inhibition of these enzymes, however, is still a very challenging goal. In this study, a novel, customized virtual screening protocol was developed with the intention of providing an efficient tool for the discovery of subtype selective JAK2 inhibitors. The screening protocol involves protein ensemble-based docking calculations combined with an Interaction Fingerprint (IFP) based scoring scheme for estimating ligand affinities and selectivities, respectively. The methodology was validated in retrospective studies and was applied prospectively to screen a large database of commercially available compounds. Six compounds were identified and confirmed in vitro, with an indazole-based hit exhibiting promising selectivity for JAK2 vs JAK1. Having demonstrated that the described methodology is capable of identifying subtype selective chemical starting points with a favorable hit rate (11%), we believe that the presented screening concept can be useful for other kinase targets with challenging selectivity profiles.
authors.affiliation: Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences , Magyar tudósok krt. 2., Budapest 1117, Hungary.
authors.forename: Dávid
authors.initials: D
authors.lastname: Bajusz
authors.affiliation: Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences , Magyar tudósok krt. 2., Budapest 1117, Hungary.
authors.forename: György G
authors.initials: GG
authors.lastname: Ferenczy
authors.affiliation: Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences , Magyar tudósok krt. 2., Budapest 1117, Hungary.
authors.forename: György M
authors.initials: GM
authors.lastname: Keserű
mesh_terms: D004353:Drug Evaluation, Preclinical / Q000379:methods*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D013379:Substrate Specificity; D014584:User-Computer Interface
chemical_list: D047428:Protein Kinase Inhibitors; D053614:Janus Kinase 2