Identification of novel PAD4 inhibitors based on a pharmacophore model derived from transition state coordinates

Yu Wei; Ruihua Liu; Cui Liu; Jin Jin; Dongmei Li; Jianping Lin

doi:10.1016/j.jmgm.2016.11.016

Identification of novel PAD4 inhibitors based on a pharmacophore model derived from transition state coordinates

J Mol Graph Model. 2017 Mar:72:88-95. doi: 10.1016/j.jmgm.2016.11.016. Epub 2016 Dec 19.

Authors

Yu Wei¹, Ruihua Liu², Cui Liu³, Jin Jin⁴, Dongmei Li⁵, Jianping Lin⁶

Affiliations

¹ 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.
² College of Life Sciences, Nankai University, Tianjin 300071, China.
³ Biodesign Center, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China.
⁴ 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.
⁵ 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.
⁶ 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.

PMID: 28064083
DOI: 10.1016/j.jmgm.2016.11.016

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 K_D (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.

Keywords: Molecular dynamic; Pharmacophore; Protein arginine deiminases; Transition state; Virtual screening.

MeSH terms

Databases, Chemical
Drug Evaluation, Preclinical
Enzyme Inhibitors / pharmacology*
Molecular Docking Simulation
Molecular Dynamics Simulation*
Protein-Arginine Deiminase Type 4
Protein-Arginine Deiminases / antagonists & inhibitors*
Protein-Arginine Deiminases / chemistry
Surface Plasmon Resonance

Substances

Enzyme Inhibitors
Protein-Arginine Deiminase Type 4
Protein-Arginine Deiminases