title: Identification of novel PAD4 inhibitors based on a pharmacophore model derived from transition state coordinates.
abstract: 1.4 Protein arginine deiminases 4 (PAD4) is an attractive target for the development of novel and selective inhibitors of Rheumatoid Arthritis (RA). F-amidine is known as mechanism-based inhibitor targeting PAD4 and used as inactivators by covalently modifying the active site Cys645. To identify novel structural inhibitors of PAD4, we investigated the flexibility of protein on basis of the transition state geometry of PAD4 inhibited by F-amidine from our previous QM/MM calculation. And a pharmacophore model was generated containing four features (ADHH) using five representative structures from molecular dynamic (MD) simulation on basis of the transition state geometry of PAD4 inhibited by F-amidine. We performed virtual screening using the pharmacophore model and molecular docking methods, resulting in the discovery of two molecules with KD(dissociation equilibrium constant) values of 112μM and 218μΜ against PAD4 through Surface Plasmon Resonance (SPR) experiments. These two molecules could potentially serve as PAD4 inhibitors.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wei
authors.affiliation: College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Ruihua
authors.initials: R
authors.lastname: Liu
authors.affiliation: Biodesign Center, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China.
authors.forename: Cui
authors.initials: C
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, China. Electronic address: jinj@nankai.edu.cn.
authors.forename: Jin
authors.initials: J
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, China. Electronic address: dongmeili@nankai.edu.cn.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Li
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, China; Biodesign Center, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China. Electronic address: jianpinglin@nankai.edu.cn.
authors.forename: Jianping
authors.initials: J
authors.lastname: Lin
mesh_terms: D062126:Databases, Chemical; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020349:Surface Plasmon Resonance
chemical_list: D004791:Enzyme Inhibitors; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases
keywords: Molecular dynamic; Pharmacophore; Protein arginine deiminases; Transition state; Virtual screening