Design and synthesis of novel PARP-1 inhibitors based on pyridopyridazinone scaffold |
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| Institution: | 1. New Drug Research & Development Center, North China Pharmaceutical Group Corporation, Shijiazhuang 050015, Hebei, China;2. National Microbial Medicine Engineering & Research Center, Shijiazhuang 050015, Hebei, China;3. Hebei Industry Microbial Metabolic Engineering & Technology Research Center, Shijiazhuang 050015, Hebei, China;4. Key Laboratory for New Drug Screening Technology of Shijiazhuang City, Shijiazhuang 050015, Hebei, China;1. Department of Chemistry, Tsinghua University, Beijing 100084, PR China;2. The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China;3. Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, PR China;4. National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China;5. Bioinformatics and Drug Design Group, Department of Pharmacy, Centre for Computational Science and Engineering, National University of Singapore, 117543, Singapore;1. Department of Chemistry, Tsinghua University, Beijing 100084, China;2. The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China;3. College of Chemistry and Chemical Engineering, Shenzhen University, Shenzhen 518060, China;4. Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China;1. Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China;2. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 21009, China;3. School of Engineering, China Pharmaceutical University, Nanjing 21009, China |
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| Abstract: | Various pyridopyridazinone derivatives were designed as Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. The pyridopyridazinone scaffold was used as an isostere of the phthalazine nucleus of the lead compound Olaparib in addition to some modifications in the tail part of the molecule. Preliminary biological evaluation indicated that most compounds possessed inhibitory potencies comparable to Olaparib in nanomolar level. The best PARP-1 inhibitory activity was observed for compound 8a with (IC50 = 36 nM) compared to Olaparib as a reference drug (IC50 = 34 nM). Molecular modeling simulation revealed that, the designed compounds docked well into PARP-1 active site and their complexes are stabilized by three key hydrogen bond interactions with both Gly863 and Ser904 as well as other favorable π-π and hydrogen-π stacking interactions with Tyr907 and Tyr896, respectively. Computational ADME study predicted that the target compounds 8a and 8e have proper pharmacokinetic and drug-likeness properties. These outcomes afford a new structural framework for the design of novel inhibitors for PARP-1. |
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| Keywords: | Pyridopyridazinones PARP-1 inhibitors Olaparib Molecular docking |
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