title: Inhibitor design against JNK1 through e-pharmacophore modeling docking and molecular dynamics simulations.
abstract: c-Jun-NH2 terminal kinases (JNKs) come under a class of serine/threonine protein kinases and are encoded by three genes, namely JNK1, JNK2 and JNK3. Human JNK1 is a cytosolic kinase belonging to mitogen-activated protein kinase (MAPK) family, which plays a major role in intracrinal signal transduction cascade mechanism. Overexpressed human JNK1, a key kinase interacts with other kinases involved in the etiology of many cancers, such as skin cancer, liver cancer, breast cancer, brain tumors, leukemia, multiple myeloma and lymphoma. Thus, to unveil a novel human JNK1 antagonist, receptor-based pharmacophore modeling was performed with the available eighteen cocrystal structures of JNK1 in the protein data bank. Eighteen e-pharmacophores were generated from the 18 cocrystal structures. Four common e-pharmacophores were developed from the 18 e-pharmacophores, which were used as three-dimensional (3D) query for shape-based similarity screening against more than one million small molecules to generate a JNK1 ligand library. Rigid receptor docking (RRD) performed using GLIDE v6.3 for the 1683 compounds from in-house library and 18 cocrystal ligands with human JNK1 from lower stringency to higher stringency revealed 17 leads. Further to derive the best leads, dock complexes obtained from RRD were studied further with quantum-polarized ligand docking (QPLD), induced fit docking (IFD) and molecular mechanics/generalized Born surface area (MM-GBSA). Four leads have showed lesser binding free energy and better binding affinity towards JNK1 compared to 18 cocrystal ligands. Additionally, JNK1-lead1 complex interaction stability was reasserted using 50 ns MD simulations run and also compared with the best resolute cocrystal structure using Desmond v3.8. Thus, the results obtained from RRD, QPLD, IFD and MD simulations indicated that lead1 might be used as a potent antagonist toward human JNK1 in cancer therapeutics.
authors.affiliation: a Department of Bioinformatics, Bioinformatics Center , SVIMS University , Tirupati , Andhra Pradesh , India.
authors.forename: Sudheer Kumar
authors.initials: SK
authors.lastname: Katari
authors.affiliation: a Department of Bioinformatics, Bioinformatics Center , SVIMS University , Tirupati , Andhra Pradesh , India.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Natarajan
authors.affiliation: a Department of Bioinformatics, Bioinformatics Center , SVIMS University , Tirupati , Andhra Pradesh , India.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Swargam
authors.affiliation: a Department of Bioinformatics, Bioinformatics Center , SVIMS University , Tirupati , Andhra Pradesh , India.
authors.forename: Hema
authors.initials: H
authors.lastname: Kanipakam
authors.affiliation: a Department of Bioinformatics, Bioinformatics Center , SVIMS University , Tirupati , Andhra Pradesh , India.
authors.forename: Chiranjeevi
authors.initials: C
authors.lastname: Pasala
authors.affiliation: a Department of Bioinformatics, Bioinformatics Center , SVIMS University , Tirupati , Andhra Pradesh , India.
authors.forename: Amineni
authors.initials: A
authors.lastname: Umamaheswari
mesh_terms: D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D020935:MAP Kinase Signaling System; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D048056:Mitogen-Activated Protein Kinase 9 / Q000037:antagonists & inhibitors / Q000737:chemistry; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D054852:Small Molecule Libraries; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8
keywords: JNK1; MD simulations; cancer; e-pharmacophore; molecular docking