Identification of Potent Chloride Intracellular Channel Protein 1 Inhibitors from Traditional Chinese Medicine through Structure-Based Virtual Screening and Molecular Dynamics Analysis.

Wei Wang,Weiqiang Yin,Jianxing He,Guilin Peng,Minghui Wan,Guixin Guo,Weide Zhong,Dongjiang Liao,Xin Xu,Funeng Jiang

doi:10.1155/2017/4751780

Abstract

Chloride intracellular channel 1 (CLIC1) is involved in the development of most aggressive human tumors, including gastric, colon, lung, liver, and glioblastoma cancers. It has become an attractive new therapeutic target for several types of cancer. In this work, we aim to identify natural products as potent CLIC1 inhibitors from Traditional Chinese Medicine (TCM) database using structure-based virtual screening and molecular dynamics (MD) simulation. First, structure-based docking was employed to screen the refined TCM database and the top 500 TCM compounds were obtained and reranked by X-Score. Then, 30 potent hits were achieved from the top 500 TCM compounds using cluster and ligand-protein interaction analysis. Finally, MD simulation was employed to validate the stability of interactions between each hit and CLIC1 protein from docking simulation, and Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) analysis was used to refine the virtual hits. Six TCM compounds with top MM-GBSA scores and ideal-binding models were confirmed as the final hits. Our study provides information about the interaction between TCM compounds and CLIC1 protein, which may be helpful for further experimental investigations. In addition, the top 6 natural products structural scaffolds could serve as building blocks in designing drug-like molecules for CLIC1 inhibition.

Highlights

Chloride intracellular channel 1 (CLIC1), a newly discovered member of the highly evolutionarily conserved CLIC family of chloride ion channel proteins, was first cloned because of its increased expression in activated macrophages [1]
CLIC1 located within the plasma membrane and other internal cell membranes are involved in diverse physiological processes [2, 3]
We employed the Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) method encoded in Amber 12 to calculate the ligand binding free energies and rescore the docking hits

Summary

Introduction

Chloride intracellular channel 1 (CLIC1), a newly discovered member of the highly evolutionarily conserved CLIC family of chloride ion channel proteins, was first cloned because of its increased expression in activated macrophages [1]. The CLIC family have seven members: CLIC1 (NCC27), CLIC2, CLIC3, CLIC4, and CLIC5A whose sequences are highly conserved across species and two larger variants, CLIC5B and CLIC6 [4, 5]. They are known to participate in many physiological processes, the control of absorption and secretion of salt, acidification of organelles, and the regulation of cell volume and membrane potentials [6]. Malfunction of any of these channel proteins can lead to severe disease states [7].

Objectives

Methods

Results