{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T03:17:15Z","timestamp":1789615035660,"version":"build-2803163510"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T00:00:00Z","timestamp":1736380800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    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 successfully identified seven hits, namely cis-Grossamide K, Daturafoliside O, N-cis-feruloyltyramine, Maceneolignan H, Erythro-2-(4-allyl-2, 6-dimethoxyphenoxy)-1-(3, 4, 5-trimethoxyphenyl) propan-1, 3-diol, Myrifralignan C, and stigmasteryl-3-O-\u03b2-glucoside as potential PDGFRA inhibitors. Not only the top 7 hits exhibited higher docking scores in docking simulation but also optimal drug-likeness 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-cis-feruloyltyramine 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\n                    <jats:italic>in-vitro<\/jats:italic>\n                    and\n                    <jats:italic>in-vivo<\/jats:italic>\n                    studies to confirm the potential of our hits for the discovery of novel therapeutics against the thyroid cancer.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2024.1512864","type":"journal-article","created":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T01:13:51Z","timestamp":1736385231000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Computer-assisted discovery of natural inhibitors for platelet-derived growth factor alpha as novel therapeutics for thyroid cancer"],"prefix":"10.3389","volume":"15","author":[{"given":"Hira","family":"Khalid","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farah","family":"Sattar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iqra","family":"Ahmad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valdir Ferreira de Paula","family":"Junior","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umar","family":"Nishan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riaz","family":"Ullah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Dib","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khaled W.","family":"Omari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohibullah","family":"Shah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,1,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"Gromacs: high performance molecular simulations through multi-level parallelism from laptops to supercomputers","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"B2","doi-asserted-by":"publisher","first-page":"16262","DOI":"10.1021\/acsomega.3c10351","article-title":"Identification of novel quinolone and quinazoline alkaloids as phosphodiesterase 10A inhibitors for Parkinson\u2019s disease through a computational approach","volume":"9","author":"Ahmad","year":"2024","journal-title":"ACS Omega"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.4065\/81.9.1241","article-title":"Biology of platelet-derived growth factor and its involvement in disease","volume":"81","author":"Alvarez","year":"2006","journal-title":"Mayo Clin. Proc."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18433\/j30k63","article-title":"Application of Caco-2 cell line in herb-drug interaction studies: current approaches and challenges","volume":"17","author":"Awortwe","year":"2014","journal-title":"J. Pharm. Pharm. Sci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"B6","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/j.foodchem.2014.09.170","article-title":"New neolignans from the seeds of Myristica fragrans that inhibit nitric oxide production","volume":"173","author":"Cao","year":"2015","journal-title":"Food Chem."},{"key":"B7","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1097\/00000658-198012000-00012","article-title":"Angiogenic activity as a marker of neoplastic and preneoplastic lesions of the human bladder","volume":"192","author":"Chodak","year":"1980","journal-title":"Ann. Surg."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1614","DOI":"10.3389\/fphar.2019.01614","article-title":"Phytochemicals in cancer treatment: from preclinical studies to clinical practice","volume":"10","author":"Choudhari","year":"2020","journal-title":"Front. Pharmacol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"10088","DOI":"10.3390\/ijms231710088","article-title":"Quantum Biochemistry and MM-PBSA description of the ZIKV NS2B-NS3 protease: insights into the binding interactions beyond the catalytic triad pocket","volume":"23","author":"de Paula Junior","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"880","DOI":"10.3390\/ph17070880","article-title":"Evaluating the physicochemical properties\u2013activity relationship and discovering new 1,2-dihydropyridine derivatives as promising inhibitors for PIM1-kinase: evidence from principal component analysis, molecular docking, and molecular dynamics studies","volume":"17","author":"Dib","year":"2024","journal-title":"Pharmaceuticals"},{"key":"B11","doi-asserted-by":"publisher","first-page":"3867","DOI":"10.1021\/jm000292e","article-title":"Prediction of drug absorption using multivariate statistics","volume":"43","author":"Egan","year":"2000","journal-title":"J. Med. Chem."},{"key":"B12","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1142\/S0219720008003618","article-title":"Compactness determines protein folding type","volume":"6","author":"Galzitskaya","year":"2008","journal-title":"J. Bioinform Comput. Biol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"741","DOI":"10.3390\/ph14080741","article-title":"In silico approaches: a way to unveil novel therapeutic drugs for cervical cancer management","volume":"14","author":"Gomes","year":"2021","journal-title":"Pharmaceuticals"},{"key":"B14","doi-asserted-by":"publisher","first-page":"2714","DOI":"10.1002\/elps.1150181505","article-title":"SWISS\u2010MODEL and the Swiss\u2010Pdb Viewer: an environment for comparative protein modeling","volume":"18","author":"Guex","year":"1997","journal-title":"Electrophoresis"},{"key":"B15","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.phytochem.2018.08.005","article-title":"Withanolides from the leaves of Datura metel L","volume":"155","author":"Guo","year":"2018","journal-title":"Phytochemistry"},{"key":"B16","doi-asserted-by":"publisher","first-page":"bvac048","DOI":"10.1210\/jendso\/bvac048","article-title":"Lenvatinib therapy for advanced thyroid cancer: real-life data on safety, efficacy, and some rare side effects","volume":"6","author":"Hamidi","year":"2022","journal-title":"J. Endocr. Soc."},{"key":"B17","doi-asserted-by":"publisher","first-page":"461","DOI":"10.3390\/ijms18020461","article-title":"Effects and side effects of using sorafenib and sunitinib in the treatment of metastatic renal cell carcinoma","volume":"18","author":"Hansen","year":"2017","journal-title":"Int. J. Mol. Sci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"4375","DOI":"10.1158\/1078-0432.CCR-12-0625","article-title":"Crenolanib inhibits the drug-resistant PDGFRA D842V mutation associated with imatinib-resistant gastrointestinal stromal tumors","volume":"18","author":"Heinrich","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"100106","DOI":"10.1016\/j.crtox.2023.100106","article-title":"Ethnobotanical uses and phytochemical, biological, and toxicological profiles of Datura metel L.: a review","volume":"4","author":"Islam","year":"2023","journal-title":"Curr. Res. Toxicol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"3313","DOI":"10.1158\/1078-0432.CCR-22-3980","article-title":"KIT and PDGFRA mutations and survival of gastrointestinal stromal tumor patients treated with adjuvant imatinib in a randomized trial","volume":"29","author":"Joensuu","year":"2023","journal-title":"Clin. Cancer Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of simple potential functions for simulating liquid water","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J. Chem. Phys."},{"key":"B22","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1002\/pro.3280","article-title":"Improvements to the APBS biomolecular solvation software suite","volume":"27","author":"Jurrus","year":"2018","journal-title":"Protein Sci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"8232","DOI":"10.3390\/ijms21218232","article-title":"Molecular modeling study of c-kit\/pdgfr\u03b1 dual inhibitors for the treatment of gastrointestinal stromal tumors","volume":"21","author":"Keretsu","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"10904","DOI":"10.1038\/s41598-024-61752-6","article-title":"Exploring optimal drug targets through subtractive proteomics analysis and pangenomic insights for tailored drug design in tuberculosis","volume":"14","author":"Khan","year":"2024","journal-title":"Sci. Rep."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1404","DOI":"10.1080\/10408398.2020.1759025","article-title":"Lignanamides: sources, biosynthesis and potential health benefits\u2013a minireview","volume":"61","author":"Leonard","year":"2021","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"B26","doi-asserted-by":"publisher","first-page":"3705","DOI":"10.3390\/molecules28093705","article-title":"The role of MMP-9 and MMP-9 inhibition in different types of thyroid carcinoma","volume":"28","author":"Li","year":"2023","journal-title":"Molecules"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1374","DOI":"10.1182\/blood-2006-02-004457","article-title":"Sorafenib is a potent inhibitor of FIP1L1-PDGFRalpha and the imatinib-resistant FIP1L1-PDGFRalpha T674I mutant","volume":"108","author":"Lierman","year":"2006","journal-title":"Blood"},{"key":"B28","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1007\/s008940100045","article-title":"GROMACS 3.0: a package for molecular simulation and trajectory analysis","volume":"7","author":"Lindahl","year":"2001","journal-title":"J. Mol. Model"},{"key":"B29","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/s0169-409x(00)00129-0","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"23","author":"Lipinski","year":"1997","journal-title":"Adv. Drug Deliv. Rev."},{"key":"B30","doi-asserted-by":"publisher","first-page":"920","DOI":"10.1002\/ana.22549","article-title":"PDGFR-\u03b1 inhibition preserves blood-brain barrier after intracerebral hemorrhage","volume":"70","author":"Ma","year":"2011","journal-title":"Ann. Neurol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"14115","DOI":"10.33263\/BRIAC116.1411514126","article-title":"Screening the efficacy of compounds from ghee to control cancer: an in silico approach","volume":"11","author":"Madhavan","year":"2021","journal-title":"Biointerface Res. Appl. Chem."},{"key":"B32","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1158\/2326-6066.CIR-13-0189","article-title":"JAK2 expression is associated with tumor-infiltrating lymphocytes and improved breast cancer outcomes: implications for evaluating JAK2 inhibitors","volume":"2","author":"Miller","year":"2014","journal-title":"Cancer Immunol. Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"9623","DOI":"10.3390\/ijms24119623","article-title":"Screening and analysis of possible drugs binding to PDGFR\u03b1: a molecular modeling study","volume":"24","author":"Mozzicafreddo","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1841","DOI":"10.1021\/jm015507e","article-title":"Simple selection criteria for drug-like chemical matter","volume":"44","author":"Muegge","year":"2001","journal-title":"J. Med. Chem."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1590\/s2175-97902020000419130","article-title":"Antidiabetic activities of alkaloids isolated from medicinal plants","volume":"57","author":"Muhammad","year":"2021","journal-title":"Braz. J. Pharm. Sci."},{"key":"B36","doi-asserted-by":"publisher","first-page":"2251099","DOI":"10.1080\/14756366.2023.2251099","article-title":"Insights into the inhibitory activities of neolignans and diarylnonanoid derivatives from nutmeg (Myristica fragrans Houtt.) seeds on soluble epoxide hydrolase using in vitro and in silico approaches","volume":"38","author":"Oanh","year":"2023","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"B37","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1021\/ci100359a","article-title":"Automated selection of compounds with physicochemical properties to maximize bioavailability and druglikeness","volume":"51","author":"Oashi","year":"2011","journal-title":"J. Chem. Inf. Model"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1385","DOI":"10.1124\/dmd.108.020479","article-title":"Trend analysis of a database of intravenous pharmacokinetic parameters in humans for 670 drug compounds","volume":"36","author":"Obach","year":"2008","journal-title":"Drug Metabolism Dispos."},{"key":"B39","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1111\/jop.12713","article-title":"PDGFRA mRNA overexpression is associated with regional metastasis and reduced survival in oral squamous cell carcinoma","volume":"47","author":"Ong","year":"2018","journal-title":"J. Oral Pathology and Med."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1349","DOI":"10.1021\/ci000383k","article-title":"Robustness of biological activity spectra predicting by computer program PASS for noncongeneric sets of chemical compounds","volume":"40","author":"Poroikov","year":"2000","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"9126","DOI":"10.33263\/BRIAC112.91269138","article-title":"Synthesis, spectral characterization, in vitro and in silico studies of Benzodioxin pyrazoline derivatives","volume":"11","author":"Prabha","year":"2021","journal-title":"Biointerface Res. Appl. Chem."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1","DOI":"10.13189\/ujfns.2013.010101","article-title":"Cytotoxic activity of ethanolic extract of myristica fragrans (Houtt) against seven human cancer cell lines","volume":"1","author":"Prakash","year":"2013","journal-title":"Univers. J. Food Nutr. Sci."},{"key":"B43","doi-asserted-by":"publisher","first-page":"134424","DOI":"10.1016\/j.molstruc.2022.134424","article-title":"Facile synthesis, pharmacological and in silico analysis of succinimide derivatives: an approach towards drug discovery","volume":"1274","author":"Rasgania","year":"2023","journal-title":"J. Mol. Struct."},{"key":"B44","doi-asserted-by":"publisher","first-page":"131","DOI":"10.3390\/vaccines11010131","article-title":"Identification of NS2B-NS3 protease inhibitors for therapeutic application in zikv infection: a pharmacophore-based high-throughput virtual screening and MD simulations approaches","volume":"11","author":"Rehman","year":"2023","journal-title":"Vaccines (Basel)"},{"key":"B45","doi-asserted-by":"publisher","first-page":"103472","DOI":"10.1016\/j.bioorg.2019.103472","article-title":"Design, synthesis, biological evaluation and molecular modeling study of new thieno[2,3-d]pyrimidines with anti-proliferative activity on pancreatic cancer cell lines","volume":"94","author":"Salem","year":"2020","journal-title":"Bioorg Chem."},{"key":"B46","volume-title":"PyMOL","author":"Schr\u00f6dinger","year":"2020"},{"key":"B47","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1016\/j.sajb.2021.09.030","article-title":"Computational analysis of plant-derived terpenes as \u03b1 -glucosidase inhibitors for the discovery of therapeutic agents against type 2 diabetes mellitus","volume":"143","author":"Shah","year":"2021","journal-title":"South Afr. J. Bot."},{"key":"B48","doi-asserted-by":"publisher","first-page":"1369659","DOI":"10.3389\/fphar.2024.1369659","article-title":"Identifying plant-derived antiviral alkaloids as dual inhibitors of SARS-CoV-2 main protease and spike glycoprotein through computational screening","volume":"15","author":"Shah","year":"","journal-title":"Front. Pharmacol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"e0294769","DOI":"10.1371\/journal.pone.0294769","article-title":"In-silico evaluation of natural alkaloids against the main protease and spike glycoprotein as potential therapeutic agents for SARS-CoV-2","volume":"19","author":"Shah","year":"","journal-title":"Plos ONE"},{"key":"B50","doi-asserted-by":"publisher","first-page":"2615","DOI":"10.1021\/jm020017n","article-title":"Molecular properties that influence the oral bioavailability of drug candidates","volume":"45","author":"Veber","year":"2002","journal-title":"J. Med. Chem."},{"key":"B51","doi-asserted-by":"publisher","first-page":"2941","DOI":"10.1007\/s42250-024-00978-3","article-title":"Versatile therapeutic potential of Swertia chirayita (roxb.) H. Karst: a review","volume":"7","author":"Verma","year":"2024","journal-title":"Chem. Afr."},{"key":"B52","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1021\/co2000168","article-title":"Atom type preferences, structural diversity, and property profiles of known drugs, leads, and nondrugs: a comparative assessment","volume":"13","author":"Viswanadhan","year":"2011","journal-title":"ACS Comb. Sci."},{"key":"B53","doi-asserted-by":"publisher","first-page":"603","DOI":"10.3390\/MD18120603","article-title":"Screening of human CYP1A2 and CYP3A4 inhibitors from seaweed in silico and in vitro","volume":"18","author":"Yim","year":"2020","journal-title":"Mar. Drugs"},{"key":"B54","doi-asserted-by":"publisher","first-page":"883581","DOI":"10.3389\/fphar.2022.883581","article-title":"In silico screening and validation of PDGFRA inhibitors enhancing radioiodine sensitivity in thyroid cancer","volume":"13","author":"Yu","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B55","first-page":"1","volume-title":"Integration of UPLC-Q-TOF-MS\/MS, chemometrics and network pharmacology to discovery potential quality markers in Sinomenii Caulis","author":"Zhang","year":"2023"},{"key":"B56","doi-asserted-by":"publisher","first-page":"1399","DOI":"10.1177\/1934578x1501000822","article-title":"Antioxidant and antiinflammatory compounds in nutmeg (myristica fragrans) pericarp as determined by in vitro assays","volume":"10","author":"Zhanga","year":"2015","journal-title":"Nat. Prod. Commun."},{"key":"B57","first-page":"187","article-title":"Lenvantinib: a tyrosine kinase inhibitor of vegfr 1-3, fgfr 1-4, PDGFR\u03b1, kit and ret","volume-title":"Recent results in cancer research","author":"Zsch\u00e4bitz","year":"2018"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1512864\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T01:13:56Z","timestamp":1736385236000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1512864\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,9]]},"references-count":57,"alternative-id":["10.3389\/fphar.2024.1512864"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2024.1512864","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,9]]},"article-number":"1512864"}}