Issue 21, 2022, Issue in Progress

Discovery of Cobimetinib as a novel A-FABP inhibitor using machine learning and molecular docking-based virtual screening

Abstract

Adipocyte fatty acid-binding protein (A-FABP, also called FABP4, aP2) is an adipokine identified as a critical regulator of metabolic function due to its dual functions of fatty acid transport and pro-inflammation. Because of the high therapeutic potential of A-FABP inhibition for the treatment of metabolic diseases and related vascular complications, numerous inhibitors have been developed against A-FABP. However, none of these inhibitors have been approved for use in patients due to severe side effects. Here, we used a virtual screening (VS) strategy to identify potential inhibitors of A-FABP in the latest FDA-approved drug library (∼2600 compounds), aiming to explore the existing drugs with proven safety profiles. We firstly combined ligand-based machine learning and structure-based molecular docking to develop a screening pipeline for identifying A-FABP inhibitors. The screening of FDA-approved drugs identified four compounds (Cobimetinib, Larotrectinib, Pantoprazole, and Vildagliptin) with the highest scores, whose inhibitory effects on A-FABP were further assessed in cellular assays. Among the selected compounds, Cobimetinib significantly inhibited the activation of the JNK/c-Jun signaling pathway by A-FABP in mouse macrophages without causing obvious cytotoxicity. In summary, we present an integrated VS pipeline for A-FABP inhibitor screening, and identified Cobimetinib as a novel A-FABP inhibitor that may be repurposed for the treatment of metabolic diseases and associated vascular complications.

Graphical abstract: Discovery of Cobimetinib as a novel A-FABP inhibitor using machine learning and molecular docking-based virtual screening

Supplementary files

Article information

Article type
Paper
Submitted
17 Feb 2022
Accepted
25 Mar 2022
First published
04 May 2022
This article is Open Access
Creative Commons BY-NC license

RSC Adv., 2022,12, 13500-13510

Discovery of Cobimetinib as a novel A-FABP inhibitor using machine learning and molecular docking-based virtual screening

S. Yang, S. Li and J. Chang, RSC Adv., 2022, 12, 13500 DOI: 10.1039/D2RA01057G

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. You can use material from this article in other publications, without requesting further permission from the RSC, provided that the correct acknowledgement is given and it is not used for commercial purposes.

To request permission to reproduce material from this article in a commercial publication, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party commercial publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements