title: Identification and validation of novel PERK inhibitors.
abstract: PERK, as one of the principle unfolded protein response signal transducers, is believed to be associated with many human diseases, such as cancer and type-II diabetes. There has been increasing effort to discover potent PERK inhibitors due to its potential therapeutic interest. In this study, a computer-based virtual screening approach is employed to discover novel PERK inhibitors, followed by experimental validation. Using a focused library, we show that a consensus approach, combining pharmacophore modeling and docking, can be more cost-effective than using either approach alone. It is also demonstrated that the conformational flexibility near the active site is an important consideration in structure-based docking and can be addressed by using molecular dynamics. The consensus approach has further been applied to screen the ZINC lead-like database, resulting in the identification of 10 active compounds, two of which show IC50 values that are less than 10 μM in a dose-response assay.
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin , Austin, Texas 78712, United States.
authors.forename: Qiantao
authors.initials: Q
authors.lastname: Wang
authors.forename: Jihyun
authors.initials: J
authors.lastname: Park
authors.forename: Ashwini K
authors.initials: AK
authors.lastname: Devkota
authors.forename: Eun Jeong
authors.initials: EJ
authors.lastname: Cho
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Dalby
authors.forename: Pengyu
authors.initials: P
authors.lastname: Ren
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D062313:Databases, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D020128:Inhibitory Concentration 50; D051379:Mice; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D015203:Reproducibility of Results; D014584:User-Computer Interface; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D019892:eIF-2 Kinase
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