Virtual screening of B-Raf kinase inhibitors: A combination of pharmacophore modelling, molecular docking, 3D-QSAR model and binding free energy calculation studies

Wen Zhang; Kai-Xiong Qiu; Fang Yu; Xiao-Guang Xie; Shu-Qun Zhang; Ya-Juan Chen; Hui-Ding Xie

doi:10.1016/j.compbiolchem.2017.08.017

Virtual screening of B-Raf kinase inhibitors: A combination of pharmacophore modelling, molecular docking, 3D-QSAR model and binding free energy calculation studies

Comput Biol Chem. 2017 Oct:70:186-190. doi: 10.1016/j.compbiolchem.2017.08.017. Epub 2017 Aug 31.

Authors

Wen Zhang¹, Kai-Xiong Qiu², Fang Yu³, Xiao-Guang Xie⁴, Shu-Qun Zhang⁵, Ya-Juan Chen⁶, Hui-Ding Xie⁷

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan, 650500, PR China. Electronic address: cherish_719@sina.com.
² Department of Medicinal Chemistry, School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan, 650500, PR China. Electronic address: chenneyao16@hotmail.com.
³ Department of Medicinal Chemistry, School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan, 650500, PR China. Electronic address: yufang519@163.com.
⁴ Department of Chemistry, Yunnan University, Kunming, Yunnan, 650091, PR China. Electronic address: xgxie@ynu.edu.cn.
⁵ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Kunming, Yunnan, 650201, PR China. Electronic address: zhangshuqun@mail.kib.ac.cn.
⁶ Department of Medicinal Chemistry, School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan, 650500, PR China. Electronic address: Chenyajuan0873@163.com.
⁷ Department of Medicinal Chemistry, School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan, 650500, PR China. Electronic address: front701228.student@sina.com.

PMID: 28892749
DOI: 10.1016/j.compbiolchem.2017.08.017

Abstract

B-Raf kinase has been identified as an important target in recent cancer treatment. In order to discover structurally diverse and novel B-Raf inhibitors (BRIs), a virtual screening of BRIs against ZINC database was performed by using a combination of pharmacophore modelling, molecular docking, 3D-QSAR model and binding free energy (ΔG_bind) calculation studies in this work. After the virtual screening, six promising hit compounds were obtained, which were then tested for inhibitory activities of A375 cell lines. In the result, five hit compounds show good biological activities (IC₅₀<50μM). The present method of virtual screening can be applied to find structurally diverse inhibitors, and the obtained five structurally diverse compounds are expected to develop novel BRIs.

Keywords: 3D QSAR; B-Raf kinase inhibitors; Binding free energy calculation; Molecular docking; Pharmacophore; Virtual screening.

MeSH terms

Algorithms*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Screening Assays, Antitumor*
Humans
Molecular Docking Simulation*
Molecular Structure
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
Proto-Oncogene Proteins B-raf / genetics
Proto-Oncogene Proteins B-raf / metabolism
Quantitative Structure-Activity Relationship*
Thermodynamics*

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Proto-Oncogene Proteins B-raf