ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1619639
This article is part of the Research TopicDiscovery of Small Molecule Lead Compounds: a Driving Force to Unravel New Anti-Cancer Targets and Mechanisms - Volume IIIView all 6 articles
In Silico Repurposing of FDA-Approved Drugs Against MEK1: Structural and Dynamic Insights into lung Cancer Therapeutics
Provisionally accepted
- 1Ajman University, Ajman, United Arab Emirates
- 2King saud University, Riyadh, Saudi Arabia
- 3Northwestern University, Chicago, United States
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
The dual specificity mitogen-activated protein kinase kinase 1 (MEK1) is a critical node in the RAS-RAF-MEK-ERK signaling pathway, frequently dysregulated in cancers due to mutations in upstream regulators. Despite the development of MEK inhibitors, challenges such as on-target toxicities and drug resistance persist that emphasize the need for novel therapeutic strategies. Drug repurposing offers a fast and cost-effective alternative by leveraging existing FDA-approved compounds with established safety profiles. This study employed computational approaches to identify repurposed MEK1 inhibitors through structure-based virtual screening of 3,500 FDA-approved drugs. The MEK1 crystal structure was subjected to molecular docking using InstaDock, followed by biological activity prediction, interaction analysis, and 500-ns molecular dynamics (MD) simulations to assess stability. Radotinib and Alectinib exhibited superior docking scores (−10.5 and −10.2 kcal/mol), outperforming the reference MEK1 inhibitor Selumetinib (−7.2 kcal/mol). MD simulations revealed stable drug complexes, with lower root mean square deviation (RMSD) and fluctuations (RMSF) than Selumetinib. Principal component analysis and free energy landscapes corroborated their conformational stability, suggesting robust binding to MEK1’s allosteric pocket. Radotinib interacted extensively with key residues, including Gly79 and Lys97 at the ATP-binding site, while Alectinib engaged critical residues such as Arg189 and His239. Their superior binding and conformational stability suggest the potential to overcome resistance and toxicity issues associated with existing MEK inhibitors. The structural and dynamic superiority of Radotinib and Alectinib over Selumetinib positions them as promising repurposed MEK1 inhibitors, potentially circumventing the clinical challenges of existing therapies. A limitation of this in silico study is the absence of experimental validation, which will be addressed in future work. Experimental validation is essential to confirm their efficacy and safety in MEK1-linked malignancies.
Keywords: Dual specificity mitogen-activated protein kinase kinase 1, Cancer, drug repurposing, small molecule inhibitors, Virtual Screening
Received: 28 Apr 2025; Accepted: 19 Aug 2025.
Copyright: © 2025 Shamsi, Khan, Zuberi and Shahwan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Anas Shamsi, Ajman University, Ajman, United Arab Emirates
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.