title: Structure-based modelling, scoring, screening, and in vitro kinase assay of anesthetic pkc inhibitors against a natural medicine library.
abstract: Protein kinase C (PKC) is an intracellular effector of the inositol phosphate-mediated signal transduction pathway. Evidence is emerging that certain general anaesthetics can influence the activity of PKC by interacting with the regulatory domain of the enzyme, and targeting PKC kinase domain is considered as a strategy to modulate the anaesthetic effects. Here, an integrated method was used to perform virtual screening against a large library of natural compounds for the discovery of new and potent PKC modulators. A number of hits were identified and their inhibitory activity against PKC kinase domain was measured by using a standard kinase assay protocol. Three and five compounds were determined to have high and moderate activities with IC50values at nanomolar and micromolar levels, respectively. These compounds can be considered as promising lead molecular entities to develop efficacious anaesthetic modulators. Structural examination revealed a variety of nonbonded interactions such as hydrogen bonds, cation-π contacts, and hydrophobic forces across the complex interface of PKC with the identified compounds. This study helps to establish an integrative approach to rational kinase inhibitor discovery by efficiently exploiting various existing natural products.
authors.affiliation: a Department of Pharmacy , Liyang People's Hospital , Liyang , China.
authors.forename: B X
authors.initials: BX
authors.lastname: Shi
authors.affiliation: a Department of Pharmacy , Liyang People's Hospital , Liyang , China.
authors.forename: F R
authors.initials: FR
authors.lastname: Chen
authors.affiliation: a Department of Pharmacy , Liyang People's Hospital , Liyang , China.
authors.forename: X
authors.initials: X
authors.lastname: Sun
mesh_terms: D000777:Anesthetics / Q000737:chemistry* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000777:Anesthetics; D047428:Protein Kinase Inhibitors; D011493:Protein Kinase C
keywords: Protein kinase C; anaesthetics; molecular modelling; natural medicine; rational drug discovery