Inhibitor screening for volume-sensitive LRRC8A chloride channel

Liu, Chao1,2; Cui, Wenqiang3; Zhu, Kongfu1; Yuan, Shuguang3; Sun, Liang4; Liang, Yujie5; Lu, Jianping5; Li, Da2; Deng, Zhiqin6; Duan, Li7; Zhang, Weiming1; Yu, Xiaohai1; Wang, Daping1,7; Zhang, Huawei2,3

2023-10-01

10.1080/07391102.2023.2274521

JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS   影响因子和分区

0739-1102

1538-0254

Leucine-rich repeat-containing protein 8 A (LRRC8A) protein is a critical member of volume-regulated anion channels. It plays a critical roles in the regulation of cellular volume and involves in the development of diseases like osteoarthritis. Screening of lead compounds to modulate its function may provide potential therapeutics of related diseases. Here, we employ virtual screening techniques and molecular dynamics (MD) simulation to screen potential inhibitors against LRRC8A. LRRC8A was regarded as the drug target to investigate potential compounds from the ZINC15 database via molecular docking. The final compound was selected among the top 10 Autodock Vina score (-8.8 Kcal/mol) with the ZINC ID ZINC000018195627 after druggability prediction. The docked complex from the virtual screening was subjected to MD simulation to analyze the stability of the LRRC8A protein-ligand complex, with parameters including root mean square deviation, root mean square fluctuation and radius of gyration. Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method was further employed to predict the binding free energies from MD simulation trajectory. Our study provides insightful analysis for the potential compound to modulate LRRC8A and lay the foundation of therapeutics development against osteoarthritis.Communicated by Ramaswamy H. Sarma

Virtual screening molecular dynamics docking MM/PBSA LRRC8A osteoarthritis

SCI

英语

通讯

National Natural Science Foundation of China["31900046","81972085","82172465"] ; Guangdong Provincial Key Laboratory of Advanced Biomaterials[2022B1212010003]

Biochemistry & Molecular Biology ; Biophysics

Biochemistry & Molecular Biology ; Biophysics

WOS:001095583400001

TAYLOR & FRANCIS INC

BIOLOGY & BIOCHEMISTRY

Web of Science

1.Dongguan City Univ, Sch Artificial Intelligence, Dept Comp Sci, Dongguan, Peoples R China
2.Southern Univ Sci & Technol, Dept Biomed Engn, Shenzhen, Peoples R China
3.Chinese Acad Sci, Shenzhen Inst Adv Technol, Res Ctr Comp Aided Drug Discovery, Shenzhen, Peoples R China
4.Shenzhen Shuli Tech Co Ltd, Shenzhen, Peoples R China
5.Shenzhen Kangning Hosp, Shenzhen Mental Hlth Ctr, Dept Child & Adolescent Psychiat, Shenzhen, Peoples R China
6.Shenzhen Univ, Shenzhen Peoples Hosp 2, Affiliated Hosp 1, Hand & Foot Surg Dept, Shenzhen, Peoples R China
7.Shenzhen Univ, Guangdong Prov Res Ctr Artificial Intelligence & D, Shenzhen Intelligent Orthopaed & Biomed Innovat Pl, Shenzhen Peoples Hosp 2,Dept Orthoped,Affiliated H, Shenzhen, Peoples R China

Liu, Chao,Cui, Wenqiang,Zhu, Kongfu,et al. Inhibitor screening for volume-sensitive LRRC8A chloride channel[J]. JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS,2023.

Liu, Chao.,Cui, Wenqiang.,Zhu, Kongfu.,Yuan, Shuguang.,Sun, Liang.,...&Zhang, Huawei.(2023).Inhibitor screening for volume-sensitive LRRC8A chloride channel.JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS.

Liu, Chao,et al."Inhibitor screening for volume-sensitive LRRC8A chloride channel".JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS (2023).