title: Pharmacophore and docking-based virtual screening approach for the design of new dual inhibitors of Janus kinase 1 and Janus kinase 2.
abstract: Janus kinase 1 and 2, non-receptor protein tyrosine kinases, are implicated in various cancerous diseases. Involvement of these two enzymes in the pathways that stimulate cell proliferation in cancerous conditions makes them potential therapeutic targets for designing new dual-targeted agents for the treatment of cancer. In the present study, two separate pharmacophore models were developed and the best models for JAK1 (AAADH.25) and JAK2 (ADRR.92) were selected on the basis of their external predictive ability. Both models were subjected to a systematic virtual screening (VS) protocol using a PHASE database of 1.5 million molecules. The hits retrieved in VS were investigated for ADME properties to avoid selection of molecules with a poor pharmacokinetic profile. The molecules considered to be within the range of acceptable limits of ADME properties were further employed for docking simulations with JAK1 and JAK2 proteins to explore the final hits that possess structural features of both pharmacophore models as well as display essential interactions with both of them. Thus, the new molecules obtained in this way should show inhibitory activity against JAK1 and JAK2 and may serve as novel therapeutic agents for the treatment of cancerous disease conditions.
authors.affiliation: a Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research , Punjabi University , Patiala , India.
authors.forename: H
authors.initials: H
authors.lastname: Jasuja
authors.forename: N
authors.initials: N
authors.lastname: Chadha
authors.forename: M
authors.initials: M
authors.lastname: Kaur
authors.forename: O
authors.initials: O
authors.lastname: Silakari
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D053613:Janus Kinase 1; D053614:Janus Kinase 2
keywords: Janus kinase 1; Janus kinase 2; Prime MM/GBSA; cancer; docking; pharmacophore