title: Weak-binding molecules are not drugs?-toward a systematic strategy for finding effective weak-binding drugs.
abstract: Designing maximally selective ligands that act on individual drug targets with high binding affinity has been the central dogma of drug discovery and development for the past two decades. However, many low-affinity drugs that aim for several targets at the same time are found more effective than the high-affinity binders when faced with complex disease conditions, such as cancers, Alzheimer's disease and cardiovascular diseases. The aim of this study was to appreciate the importance and reveal the features of weak-binding drugs and propose an integrated strategy for discovering them. Weak-binding drugs can be characterized by their high dissociation rates and transient interactions with their targets. In addition, network topologies and dynamics parameters involved in the targets of weak-binding drugs also influence the effects of the drugs. Here, we first performed a dynamics analysis for 33 elementary subgraphs to determine the desirable topology and dynamics parameters among targets. Then, by applying the elementary subgraphs to the mitogen-activated protein kinase (MAPK) pathway, several optimal target combinations were obtained. Combining drug-target interaction prediction with molecular dynamics simulation, we got two potential weak-binding drug candidates, luteolin and tanshinone IIA, acting on these targets. Further, the binding affinity of these two compounds to their targets and the anti-inflammatory effects of them were validated through in vitro experiments. In conclusion, weak-binding drugs have real opportunities for maximum efficiency and may show reduced adverse reactions, which can offer a bright and promising future for new drug discovery.
authors.affiliation: Lab of Systems Pharmacology, Center of Bioinformatics, College of Life Science, Northwest A&F University, Yangling, Shaanxi, China, School of Chemical engineering, Dalian University of Technology, Dalian, Liaoning, China, Beijing University of Chinese Medicine, ChaoYang District, Beijing, China and School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Jinan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Lab of Systems Pharmacology, Center of Bioinformatics, College of Life Science, Northwest A&F University, Yangling, Shaanxi, China, School of Chemical engineering, Dalian University of Technology, Dalian, Liaoning, China, Beijing University of Chinese Medicine, ChaoYang District, Beijing, China and School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Zihu
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Lab of Systems Pharmacology, Center of Bioinformatics, College of Life Science, Northwest A&F University, Yangling, Shaanxi, China, School of Chemical engineering, Dalian University of Technology, Dalian, Liaoning, China, Beijing University of Chinese Medicine, ChaoYang District, Beijing, China and School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Yingxue
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Lab of Systems Pharmacology, Center of Bioinformatics, College of Life Science, Northwest A&F University, Yangling, Shaanxi, China, School of Chemical engineering, Dalian University of Technology, Dalian, Liaoning, China, Beijing University of Chinese Medicine, ChaoYang District, Beijing, China and School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Ziyin
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Lab of Systems Pharmacology, Center of Bioinformatics, College of Life Science, Northwest A&F University, Yangling, Shaanxi, China, School of Chemical engineering, Dalian University of Technology, Dalian, Liaoning, China, Beijing University of Chinese Medicine, ChaoYang District, Beijing, China and School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Chao
authors.initials: C
authors.lastname: Huang
authors.affiliation: Lab of Systems Pharmacology, Center of Bioinformatics, College of Life Science, Northwest A&F University, Yangling, Shaanxi, China, School of Chemical engineering, Dalian University of Technology, Dalian, Liaoning, China, Beijing University of Chinese Medicine, ChaoYang District, Beijing, China and School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Chunli
authors.initials: C
authors.lastname: Zheng
authors.affiliation: College of Life Science, Northwest A & F University, Yangling, Shaanxi, 712100, China; Center of Bioinformatics, Northwest A & F University, Yangling, Shaanxi, China.
authors.forename: Piar Ali
authors.initials: PA
authors.lastname: Shar
authors.affiliation: Jiangsu Kanion Pharmaceutical Co. Ltd., Lianyungang, PR China.
authors.forename: Zhenzhong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: State Key Laboratory of New-Tech for Chinese Medicine Pharmaceutical Process, Lianyungang, Jiangsu, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Lab of Systems Pharmacology, Center of Bioinformatics, College of Life Science, Northwest A&F University, Yangling, Shaanxi, China, School of Chemical engineering, Dalian University of Technology, Dalian, Liaoning, China, Beijing University of Chinese Medicine, ChaoYang District, Beijing, China and School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Wang
mesh_terms: D016503:Drug Delivery Systems; D055808:Drug Discovery; D004347:Drug Interactions; D006801:Humans; D008024:Ligands
chemical_list: D008024:Ligands
keywords: mathematical modeling; polypharmacology; systems pharmacology; weak-binding drug