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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1512864
This article is part of the Research Topic AI Research in Cancer Pharmacology View all 3 articles

Computer-assisted Discovery of Natural Inhibitors for Platelet-derived Growth Factor Alpha (PDGFRA) as Novel Therapeutics for Thyroid Cancer

Provisionally accepted
Mohibullah Shah Mohibullah Shah 1*Hira Khalid Hira Khalid 1Farah Sattar Farah Sattar 1Iqra Ahmad Iqra Ahmad 1Valdir ferreira de paula Junior Valdir ferreira de paula Junior 2Arlindo A. Moura Arlindo A. Moura 2Umar Nishan Umar Nishan 3Riaz Ullah Riaz Ullah 4Abdelaaty A Shahat Abdelaaty A Shahat 4Hanna Dib Hanna Dib 5Khaled Omari Khaled Omari 5
  • 1 Department of Biochemistry, Faculty of Sciences, Bahauddin Zakariya University, Multan, Pakistan
  • 2 Federal University of Ceara, Fortaleza, Ceará, Brazil
  • 3 Kohat University of Science and Technology, Kohat, Khyber Pakhtunkhwa, Pakistan
  • 4 King Saud University, Riyadh, Riyadh, Saudi Arabia
  • 5 American University of the Middle East, Kuwait City, Kuwait

The final, formatted version of the article will be published soon.

    Platelet-derived growth factor alpha (PDGFRA) plays a significant role in various malignant tumors. PDGFRA expression boosts thyroid cancer cell proliferation and metastasis.Radiorefractory thyroid cancer is poorly differentiated, very aggressive, and resistant to radioiodine therapy. Thus, novel anticancer drugs that inhibit its metastasis are urgently required.In this context, we proposed the PDGFRA inhibitors by an optimized structure-based drug design approach. We performed a virtual screening of metabolites derived from anticancer medicinal plants (Swertia chirayita, Myristica fragrans, and Datura metel) and identified seven hits, namely cis-Grossamide K, Daturafoliside O, N-cis-feruloyltyramine, Maceneolignan H,Myrifralignan C, and stigmasteryl-3-O-β-glucoside as potential PDGFRA inhibitors. Not only the top 7 hits exhibited higher docking scores in docking simulation but also optimal druglikeness and non-toxic profiles in pharmacokinetics analysis among 119 compounds. Our top hits are non-mutagenic, can cross the blood-brain barrier, and inhibit p-glycoprotein, while the N-cisferuloyltyramine has the potential to become a lead compound. The protein-ligand stability of the top 3 hits, namely cis-Grossamide K, Daturafoliside O, and N-cis-feruloyltyramine, and their interactions at the potential binding site of target protein were confirmed through molecular dynamic simulations. We also analyzed pharmacophoric features for stable binding in the PDGFRA active site. These drug candidates were further characterized to predict their biological activity spectra in the human body and medicinal characteristics to know their extensive behavior in laboratory testing. This study necessitates the in-vitro and in-vivo studies to confirm the potential of our hits for discovering of novel therapeutics against the thyroid cancer.

    Keywords: anticancer, Natural Products, drug design, Ethnopharmacology, Virtual Screening

    Received: 17 Oct 2024; Accepted: 17 Dec 2024.

    Copyright: © 2024 Shah, Khalid, Sattar, Ahmad, Junior, Moura, Nishan, Ullah, Shahat, Dib and Omari. 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: Mohibullah Shah, Department of Biochemistry, Faculty of Sciences, Bahauddin Zakariya University, Multan, Pakistan

    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.