Ligand-based and e-pharmacophore modeling, 3D-QSAR and hierarchical virtual screening to identify dual inhibitors of spleen tyrosine kinase (Syk) and janus kinase 3 (JAK3).
The clinical efficacy of multiple kinase inhibitors has caught the interest of Pharmaceutical and Biotech researchers to develop potential drugs with multi-kinase inhibitory activity for complex diseases. In the present work, we attempted to identify dual inhibitors of spleen tyrosine kinase (Syk) and janus kinase 3 (JAK3), keys players in immune signaling, by developing ideal pharmacophores integrating Ligand-based pharmacophore models (LBPMs) and Structure-based pharmacophore models (SBPMs), thereby projecting the optimum pharmacophoric required for inhibition of both the kinases. The four point LBPM; ADPR.14 suggested the presence of one hydrogen bond acceptor, one hydrogen bond donor, one positive ionizable, and one ring aromatic feature for Syk inhibitory activity and AADH.54 proposed the necessity of two hydrogen bond acceptor, one hydrogen bond donor, and one hydrophobic feature for JAK3 inhibitory activity. To our interest, SBPMs identified additional ring aromatic features required for inhibition of both the kinases. For Syk inhibitory activity, the hydrogen bond acceptor feature indicated by LBPM was devoid of forming hydrogen bonding interaction with the hinge region amino acid residue (Ala451). Thus merging the information revealed by both LBPMs and SBPMs, ideal pharmacophore models i.e. ADPRR.14 (Syk) and AADHR.54 (JAK3) were generated. These models after rigorous statistical validation were used for screening of Asinex database. The systematic virtual screening protocol, including pharmacophore and docking-based screening, ADME property, and MM-GBSA energy calculations, retrieved final 10 hits as dual inhibitors of Syk and JAK3. Final 10 hits thus obtained can aid in the development of potential therapeutic agents for autoimmune disorders. Also the top two hits were evaluated against both the enzymes.
a Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research , Punjabi University , Patiala , Punjab 147002 , India.
Maninder
M
Kaur
a Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research , Punjabi University , Patiala , Punjab 147002 , India.
Om
O
Silakari
D003198:Computer Simulation; D015195:Drug Design; D006860:Hydrogen Bonding; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D000072377:Syk Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry*
D008024:Ligands; D047428:Protein Kinase Inhibitors; D053616:Janus Kinase 3; D000072377:Syk Kinase
auto-immune disorders; e-pharmacophore; janus Kinase-3 (JAK3); multi-targeted; spleen tyrosine kinase (Syk)