Version 1
: Received: 2 April 2024 / Approved: 2 April 2024 / Online: 3 April 2024 (07:24:16 CEST)
How to cite:
Sakaguchi, K.; Okiyama, Y.; Tanaka, S. In Silico Search for Drug Candidates Targeting the PAX8–PPARγ Fusion Protein in Thyroid Cancer. Preprints2024, 2024040199. https://doi.org/10.20944/preprints202404.0199.v1
Sakaguchi, K.; Okiyama, Y.; Tanaka, S. In Silico Search for Drug Candidates Targeting the PAX8–PPARγ Fusion Protein in Thyroid Cancer. Preprints 2024, 2024040199. https://doi.org/10.20944/preprints202404.0199.v1
Sakaguchi, K.; Okiyama, Y.; Tanaka, S. In Silico Search for Drug Candidates Targeting the PAX8–PPARγ Fusion Protein in Thyroid Cancer. Preprints2024, 2024040199. https://doi.org/10.20944/preprints202404.0199.v1
APA Style
Sakaguchi, K., Okiyama, Y., & Tanaka, S. (2024). In Silico Search for Drug Candidates Targeting the PAX8–PPARγ Fusion Protein in Thyroid Cancer. Preprints. https://doi.org/10.20944/preprints202404.0199.v1
Chicago/Turabian Style
Sakaguchi, K., Yoshio Okiyama and Shigenori Tanaka. 2024 "In Silico Search for Drug Candidates Targeting the PAX8–PPARγ Fusion Protein in Thyroid Cancer" Preprints. https://doi.org/10.20944/preprints202404.0199.v1
Abstract
The PAX8/PPARγ rearrangement, producing the PAX8–PPARγ fusion protein (PPFP), is thought to play an essential role in the oncogenesis of thyroid follicular tumors. To identify PPFP-targeted drug candidates and establish an early standard of care for thyroid tumors, we performed ensemble docking-based compound screening. Specifically, we investigated which pocket structure should be adopted to search for a promising ligand compound for the PPFP; the position of the ligand binding pocket on the PPARγ side of the PPFP is common to that of PPARγ; however, the shape is slightly different between them due to environmental factors. We developed a method for selecting a PPFP structure with a relevant pocket and high prediction accuracy for ligand binding. This method was validated using PPARγ, whose structure and activity values are known for many compounds. Then, we performed docking calculations to PPFP for 97 drug or drug-like compounds with a thiazolidine backbone, which is one of the characteristics of ligands that bind well to PPARγ, registered in the DrugBank database. Furthermore, the binding affinities of promising ligand candidates were estimated more reliably using the molecular mechanics-Poisson–Boltzmann surface area method. Thus, we propose promising drug candidates for the PPFP with a thiazolidine backbone.
Keywords
follicular thyroid neoplasia; PAX8–PPARγ fusion; fusion protein; structure-based drug design
Subject
Medicine and Pharmacology, Oncology and Oncogenics
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
