title: Finding off-targets, biological pathways, and target diseases for chymase inhibitors via structure-based systems biology approach.
abstract: Off-target binding connotes the binding of a small molecule of therapeutic significance to a protein target in addition to the primary target for which it was proposed. Progressively such off-targeting is emerging to be regular practice to reveal side effects. Chymase is an enzyme of hydrolase class that catalyzes hydrolysis of peptide bonds. A link between heart failure and chymase is ascribed, and a chymase inhibitor is in clinical phase II for treatment of heart failure. However, the underlying mechanisms of the off-target effects of human chymase inhibitors are still unclear. Here, we develop a robust computational strategy that is applicable to any enzyme system and that allows the prediction of drug effects on biological processes. Putative off-targets for chymase inhibitors were identified through various structural and functional similarity analyses along with molecular docking studies. Finally, literature survey was performed to incorporate these off-targets into biological pathways and to establish links between pathways and particular adverse effects. Off-targets of chymase inhibitors are linked to various biological pathways such as classical and lectin pathways of complement system, intrinsic and extrinsic pathways of coagulation cascade, and fibrinolytic system. Tissue kallikreins, granzyme M, neutrophil elastase, and mesotrypsin are also identified as off-targets. These off-targets and their associated pathways are elucidated for the effects of inflammation, cancer, hemorrhage, thrombosis, and central nervous system diseases (Alzheimer's disease). Prospectively, our approach is helpful not only to better understand the mechanisms of chymase inhibitors but also for drug repurposing exercises to find novel uses for these inhibitors.
authors.affiliation: School of Biomedical Sciences, Faculty of Health Sciences, Curtin Health Innovation Research Institute (CHIRI), Curtin University, Australia.
authors.forename: Mahreen
authors.initials: M
authors.lastname: Arooj
authors.affiliation: Division of Applied Life Science (BK21 Program), Systems and Synthetic Agrobiotech Center (SSAC), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science(RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Gazha-dong, Jinju, 660-701, Republic of Korea.
authors.forename: Sugunadevi
authors.initials: S
authors.lastname: Sakkiah
authors.affiliation: Division of Applied Life Science (BK21 Program), Systems and Synthetic Agrobiotech Center (SSAC), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science(RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Gazha-dong, Jinju, 660-701, Republic of Korea.
authors.forename: Guang Ping
authors.initials: GP
authors.lastname: Cao
authors.affiliation: Division of Applied Life Science (BK21 Program), Systems and Synthetic Agrobiotech Center (SSAC), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science(RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Gazha-dong, Jinju, 660-701, Republic of Korea.
authors.forename: Songmi
authors.initials: S
authors.lastname: Kim
authors.affiliation: Division of Applied Life Science (BK21 Program), Systems and Synthetic Agrobiotech Center (SSAC), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science(RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Gazha-dong, Jinju, 660-701, Republic of Korea.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Arulalapperumal
authors.affiliation: Division of Applied Life Science (BK21 Program), Systems and Synthetic Agrobiotech Center (SSAC), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science(RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Gazha-dong, Jinju, 660-701, Republic of Korea.
authors.forename: Keun Woo
authors.initials: KW
authors.lastname: Lee
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D001777:Blood Coagulation / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D053818:Chymases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D037582:Complement Pathway, Mannose-Binding Lectin / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005342:Fibrinolysis / Q000187:drug effects; D053804:Granzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D049490:Systems Biology / Q000379:methods*; D020840:Tissue Kallikreins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D014357:Trypsin / Q000737:chemistry / Q000378:metabolism; D014584:User-Computer Interface
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; C509218:GZMM protein, human; D053804:Granzymes; D020840:Tissue Kallikreins; D019272:Leukocyte Elastase; D053818:Chymases; C040749:PRSS3 protein, human; D014357:Trypsin
keywords: Alzheimer's disease; biological pathways; cardiovascular diseases; chymase; coagulation cascade; complement system; off-targets; systems biology, cancer