title: Dual inhibitors of Janus kinase 2 and 3 (JAK2/3): designing by pharmacophore- and docking-based virtual screening approach.
abstract: JAK2 and JAK3 are non-receptor protein tyrosine kinases implicated in B-cell- and T-cell-mediated diseases. Both enzymes work via different pathways but are involved in the pathogenesis of common lymphoid-derived diseases. Hence, targeting both Janus kinases together can be a potential strategy for the treatment of these diseases. In the present study, two separate pharmacophore-based 3D-QSAR models ADRR.92 (Q(2)(test)0.663, R(2)(train) 0.849, F value 219.3) for JAK2 and ADDRR.142 (Q(2)(test)0.655, R(2)(train) 0.869, F value 206.9) for JAK3 were developed. These models were employed for the screening of a PHASE database of approximately 1.5 million compounds; subsequently, the retrieved hits were screened employing docking simulations with JAK2 and JAK3 proteins. Finally, ADME properties of screened dual inhibitors displaying essential interactions with both proteins were calculated to filter candidates with poor pharmacokinetic profiles. These candidates could serve as novel therapeutic agents in the treatment of lymphoid-related diseases.
authors.affiliation: Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala , 147002, Punjab, India.
authors.forename: Haneesh
authors.initials: H
authors.lastname: Jasuja
authors.forename: Navriti
authors.initials: N
authors.lastname: Chadha
authors.forename: Maninder
authors.initials: M
authors.lastname: Kaur
authors.forename: Om
authors.initials: O
authors.lastname: Silakari
mesh_terms: D065966:Absorption, Physicochemical; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D053614:Janus Kinase 2; D053616:Janus Kinase 3