title: Combining structure-based pharmacophore modeling, virtual screening, and in silico ADMET analysis to discover novel tetrahydro-quinoline based pyruvate kinase isozyme M2 activators with antitumor activity.
abstract: Compared with normal differentiated cells, cancer cells upregulate the expression of pyruvate kinase isozyme M2 (PKM2) to support glycolytic intermediates for anabolic processes, including the synthesis of nucleic acids, amino acids, and lipids. In this study, a combination of the structure-based pharmacophore modeling and a hybrid protocol of virtual screening methods comprised of pharmacophore model-based virtual screening, docking-based virtual screening, and in silico ADMET (absorption, distribution, metabolism, excretion and toxicity) analysis were used to retrieve novel PKM2 activators from commercially available chemical databases. Tetrahydroquinoline derivatives were identified as potential scaffolds of PKM2 activators. Thus, the hybrid virtual screening approach was applied to screen the focused tetrahydroquinoline derivatives embedded in the ZINC database. Six hit compounds were selected from the final hits and experimental studies were then performed. Compound 8 displayed a potent inhibitory effect on human lung cancer cells. Following treatment with Compound 8, cell viability, apoptosis, and reactive oxygen species (ROS) production were examined in A549 cells. Finally, we evaluated the effects of Compound 8 on mice xenograft tumor models in vivo. These results may provide important information for further research on novel PKM2 activators as antitumor agents.
authors.affiliation: State Key Laboratory of Biotherapy and Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, People's Republic of China ; College of Pharmacy and the First Affiliated Hospital, Chengdu Medical College, Chengdu, People's Republic of China.
authors.forename: Can
authors.initials: C
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Biotherapy and Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, People's Republic of China ; Department of Cardiology, General Hospital of Chengdu Military Command, Chengdu, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biotherapy and Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Fengbo
authors.initials: F
authors.lastname: Wu
authors.affiliation: State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Biotherapy and Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Gu
authors.initials: G
authors.lastname: He
authors.affiliation: State Key Laboratory of Biotherapy and Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Ouyang
authors.affiliation: State Key Laboratory of Biotherapy and Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Mingli
authors.initials: M
authors.lastname: Xiang
authors.affiliation: State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Biotherapy and Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, People's Republic of China ; College of Pharmacy and the First Affiliated Hospital, Chengdu Medical College, Chengdu, People's Republic of China.
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D013963:Thyroid Hormones / Q000378:metabolism*; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D008565:Membrane Proteins; D011804:Quinolines; D017382:Reactive Oxygen Species; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C542964:1,2,3,4-tetrahydroquinoline
keywords: molecular docking; pharmacophore; pyruvate kinase; virtual screening