Discovery and characterization of novel FAK inhibitors for breast cancer therapy via hybrid virtual screening, biological evaluation and molecular dynamics simulations

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2025-03-26 DOI:10.1016/j.bioorg.2025.108400

Xinglong Chi , Runmei Chen , Roufen Chen , Yingxuan Xu , Yaru Deng , Xinle Yang , Zhichao Pan , Xiangwei Xu , Youlu Pan , Qin Li , Peng Zhou , Wenhai Huang

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引用次数: 0

Abstract

Focal adhesion kinase (FAK) is a critical drug target implicated in various disease pathways, including hematological malignancies and breast cancer. Therefore, identifying FAK inhibitors with novel scaffolds could offer new opportunities for developing effective therapeutic compounds. Herein, we disclosed the discovery of a new backbone inhibitor of FAK using an “internal” database, employing a structure-based high-transparency permeability virtual screening (HTVS) and a DeepDock algorithm based on geometric deep learning. Subsequently, molecular docking was conducted at different precisions to identify 10 compounds for further evaluation of biological activity. Ultimately, compound 4, a pyrimidin-4-amine derivative, demonstrated inhibitory activity against FAK and breast cancer cells, further supporting its potential as a FAK inhibitor. Moreover, molecular dynamics simulations were carried out to gain more detailed insights into the binding mechanism between compound 4 and FAK to guide subsequent structural optimization.

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.