title: Repositioning organohalogen drugs: a case study for identification of potent B-Raf V600E inhibitors via docking and bioassay.
abstract: Drug repositioning has been attracting increasingly attention for its advantages of reducing costs and risks. Statistics showed that around one quarter of the marketed drugs are organohalogens. However, no study has been reported, to the best of our knowledge, to aim at efficiently repositioning organohalogen drugs, which may be attributed to the lack of accurate halogen bonding scoring function. Here, we present a study to show that two organohalogen drugs were successfully repositioned as potent B-Raf V600E inhibitors via molecular docking with halogen bonding scoring function, namely D(3)DOCKxb developed in our lab, and bioassay. After virtual screening by D(3)DOCKxb against the database CMC (Comprehensive Medicinal Chemistry), 3 organohalogen drugs that were predicted to form strong halogen bonding with B-Raf V600E were purchased and tested with ELISA-based assay. In the end, 2 of them, rafoxanide and closantel, were identified as potent inhibitors with IC50 values of 0.07 μM and 1.90 μM, respectively, which are comparable to that of vemurafenib (IC50: 0.17 μM), a marketed drug targeting B-Raf V600E. Single point mutagenesis experiments confirmed the conformations predicted by D(3)DOCKxb. And comparison experiment revealed that halogen bonding scoring function is essential for repositioning those drugs with heavy halogen atoms in their molecular structures.
authors: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.|Nano Science and Technology Institute, University of Science and Technology of China, Suzhou, Jiangsu, 215123, China.
authors: Yisu
authors: Y
authors: Li
authors: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
authors: Binbin
authors: B
authors: Guo
authors: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.|State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
authors: Zhijian
authors: Z
authors: Xu
authors: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
authors: Bo
authors: B
authors: Li
authors: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
authors: Tingting
authors: T
authors: Cai
authors: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
authors: Xinben
authors: X
authors: Zhang
authors: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
authors: Yuqi
authors: Y
authors: Yu
authors: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
authors: Heyao
authors: H
authors: Wang
authors: UCB Biopharma SPRL, Chemin du Foriest, Braine-l'Alleud, Belgium.
authors: Jiye
authors: J
authors: Shi
authors: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
authors: Weiliang
authors: W
authors: Zhu
mesh_terms: D019943:Amino Acid Substitution; D004353:Drug Evaluation, Preclinical; D058492:Drug Repositioning; D006219:Halogens / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D009930:Organic Chemicals / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011888:Rafoxanide / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D012458:Salicylanilides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D014584:User-Computer Interface
chemical_list: D006219:Halogens; D009930:Organic Chemicals; D047428:Protein Kinase Inhibitors; D012458:Salicylanilides; D011888:Rafoxanide; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C023342:closantel