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Combining pharmacophore, docking and substructure search approaches to identify and optimize novel B-RafV600E inhibitors
- Source :
- Bioorganicmedicinal chemistry letters. 22(17)
- Publication Year :
- 2012
-
Abstract
- In this study for searching novel B-Raf(V600E) inhibitors, pharmacophore-based virtual screening identified 1 as a hit bearing 5-benzylidene-2-thioxodihydropyrimidine-4,6(1H,5H)-dione. Based on 1, scaffold hopping inspired by molecular docking discovered 5-(furan-2-ylmethylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione as a new and better scaffold. Substructure search with the new scaffold identified 28 active compounds, among which 12 compounds (42.9%) showed IC(50) less than 1 μM. Especially, compound 3o, which is 10-fold more potent than the hit 1, is a potent inhibitor comparable to that of the marketed drug vemurafenib.
- Subjects :
- Proto-Oncogene Proteins B-raf
Scaffold
Molecular model
Stereochemistry
Clinical Biochemistry
Mutation, Missense
Pharmaceutical Science
Computational biology
Pyrimidinones
Biochemistry
Molecular Docking Simulation
Structure-Activity Relationship
Neoplasms
Drug Discovery
medicine
Structure–activity relationship
Humans
Vemurafenib
Molecular Biology
Protein Kinase Inhibitors
Virtual screening
Chemistry
Organic Chemistry
Amino Acid Substitution
Docking (molecular)
Drug Design
Molecular Medicine
Pharmacophore
medicine.drug
Subjects
Details
- ISSN :
- 14643405
- Volume :
- 22
- Issue :
- 17
- Database :
- OpenAIRE
- Journal :
- Bioorganicmedicinal chemistry letters
- Accession number :
- edsair.doi.dedup.....4f15cb3ec9517afb5962cf02cffe17de