title: Ligand-based and structure-based approaches in identifying ideal pharmacophore against c-Jun N-terminal kinase-3.
abstract: Structure and ligand based pharmacophore modeling and docking studies carried out using diversified set of c-Jun N-terminal kinase-3 (JNK3) inhibitors are presented in this paper. Ligand based pharmacophore model (LBPM) was developed for 106 inhibitors of JNK3 using a training set of 21 compounds to reveal structural and chemical features necessary for these molecules to inhibit JNK3. Hypo1 consisted of two hydrogen bond acceptors (HBA), one hydrogen bond donor (HBD), and a hydrophobic (HY) feature with a correlation coefficient (r²) of 0.950. This pharmacophore model was validated using test set containing 85 inhibitors and had a good r² of 0.846. All the molecules were docked using Glide software and interestingly, all the docked conformations showed hydrogen bond interactions with important hinge region amino acids (Gln155 and Met149)and these interactions were compared with Hypo1 features. The results of ligand based pharmacophore model (LBPM)and docking studies are validated each other. The structure based pharmacophore model (SBPM) studies have identified additional features, two hydrogen bond donors and one hydrogen bond acceptor. The combination of these methodologies is useful in designing ideal pharmacophore which provides a powerful tool for the discovery of novel and selective JNK3 inhibitors.
authors.affiliation: bioCampus, GVK Biosciences Private Limited, S-1, Phase-1, TIE, Balanagar, Hyderabad 500037, India.
authors.forename: B V S Suneel
authors.initials: BV
authors.lastname: Kumar
authors.forename: Rohith
authors.initials: R
authors.lastname: Kotla
authors.forename: Revanth
authors.initials: R
authors.lastname: Buddiga
authors.forename: Jyoti
authors.initials: J
authors.lastname: Roy
authors.forename: Sardar Shamshair
authors.initials: SS
authors.lastname: Singh
authors.forename: Rambabu
authors.initials: R
authors.lastname: Gundla
authors.forename: Muttineni
authors.initials: M
authors.lastname: Ravikumar
authors.forename: Jagarlapudi A R P
authors.initials: JA
authors.lastname: Sarma
mesh_terms: D020134:Catalytic Domain; D015195:Drug Design; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008024:Ligands; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D012984:Software
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D048057:Mitogen-Activated Protein Kinase 10
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