{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T17:33:14Z","timestamp":1757611994329,"version":"3.44.0"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T00:00:00Z","timestamp":1756944000000},"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:sec><jats:title>Background<\/jats:title><jats:p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that results in the degeneration of motor neurons and is typically linked to toxic aggregates of mutant superoxide dismutase 1 (SOD1) protein. As autophagy is critical for the removal of these toxic protein aggregates, stimulating autophagy has emerged as a promising therapeutic approach for ALS. Unc-51-like kinase 1 (ULK1) is a key regulator of autophagy and has been shown to have the potential to prevent ALS pathology when activated. However, synthetic ULK1 activators are frequently limited by toxicity and suboptimal pharmacokinetic profiles. This study aimed to identify natural ULK1 activators using a systematic virtual screening approach for potential ALS therapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>This study employed a comprehensive virtual screening approach to identify phytochemicals capable of activating ULK1. Natural compounds from the IMPPAT database were screened using molecular docking, followed by pan-assay interference compounds (PAINS) filtering, pharmacokinetic profiling, and density functional theory (DFT) analysis. Further, biological activity was predicted using the PASS tool, and candidate molecules were subjected to molecular dynamics (MD) simulations, essential dynamics, and binding free energy calculations via MM-PBSA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The systematic screening in this study identified Candidine and Delavinone as high-affinity binders with reference to BL-918, proposing them as potential activators of ULK1. Both compounds demonstrated favorable drug-likeness, stable interactions with ULK1 in MD simulations, and promising ALS-relevant activity profiles. Essential dynamics and MM-PBSA further supported the binding stability and energetic favorability of these interactions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Candidine and Delavinone emerge as promising phytochemical activators of ULK1 with potential therapeutic relevance for ALS. These findings warrant further experimental validation and preclinical studies to explore their efficacy in autophagy modulation and neuroprotection.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1661744","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T05:34:44Z","timestamp":1756964084000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Exploring bioactive phytochemicals as ULK1 activators for enhancing cytoprotective autophagy in amyotrophic lateral sclerosis"],"prefix":"10.3389","volume":"16","author":[{"given":"Farah","family":"Anjum","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nahed","family":"Hawsawi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdulraheem Ali","family":"Almalki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anas","family":"Shamsi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maram Jameel","family":"Hulbah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maha","family":"Bakhuraysah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdulaziz","family":"Alsharif","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taj","family":"Mohammad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1499","DOI":"10.1002\/cbic.202000695","article-title":"The perturbed free\u2010energy landscape: linking ligand binding to biomolecular folding","volume":"22","author":"Abdelsattar","year":"2021","journal-title":"ChemBioChem"},{"key":"B2","doi-asserted-by":"publisher","first-page":"3459","DOI":"10.1080\/07391102.2023.2218938","article-title":"Identification of natural product-based effective inhibitors of spleen tyrosine kinase (SYK) through virtual screening and molecular dynamics simulation approaches","volume":"42","author":"Ali","year":"2024","journal-title":"J. Biomol. Struct. Dyn."},{"key":"B3","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1002\/pro.4213","article-title":"RCSB protein data bank: celebrating 50 years of the PDB with new tools for understanding and visualizing biological macromolecules in 3D","volume":"31","author":"Burley","year":"2022","journal-title":"Protein Sci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1042\/BCJ20190038","article-title":"Conservation of structure, function and inhibitor binding in UNC-51-like kinase 1 and 2 (ULK1\/2)","volume":"476","author":"Chaikuad","year":"2019","journal-title":"Biochem. J."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1196","DOI":"10.3390\/biom13081196","article-title":"Polyphenols, autophagy and neurodegenerative diseases: a review","volume":"13","author":"Chandrasekaran","year":"2023","journal-title":"Biomolecules"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1789","DOI":"10.3390\/cells10071789","article-title":"Amyotrophic lateral sclerosis (ALS): stressed by dysfunctional mitochondria-endoplasmic reticulum contacts (MERCs)","volume":"10","author":"Chen","year":"2021","journal-title":"Cells"},{"key":"B7","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1080\/15548627.2021.1926656","article-title":"Autophagy and ALS: mechanistic insights and therapeutic implications","volume":"18","author":"Chua","year":"2022","journal-title":"Autophagy"},{"key":"B8","doi-asserted-by":"publisher","first-page":"278","DOI":"10.3390\/cells7120278","article-title":"Autophagy: an essential degradation program for cellular homeostasis and life","volume":"7","author":"Chun","year":"2018","journal-title":"Cells"},{"key":"B9","first-page":"82","article-title":"Pymol: an open-source molecular graphics tool","volume":"40","author":"DeLano","year":"2002","journal-title":"CCP4 Newsl. Protein Crystallogr."},{"key":"B10","doi-asserted-by":"publisher","first-page":"704","DOI":"10.3390\/ijms24010704","article-title":"Molecular investigations of protein aggregation in the pathogenesis of amyotrophic lateral sclerosis","volume":"24","author":"Duranti","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1007\/s00894-009-0454-9","article-title":"Solvent accessible surface area approximations for rapid and accurate protein structure prediction","volume":"15","author":"Durham","year":"2009","journal-title":"J. Mol. Model."},{"key":"B12","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.jconrel.2022.03.001","article-title":"Targeting autophagy, oxidative stress, and ER stress for neurodegenerative disease treatment","volume":"345","author":"Esmaeili","year":"2022","journal-title":"J. Control. Release"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1363","DOI":"10.1016\/S0140-6736(22)01272-7","article-title":"Amyotrophic lateral sclerosis","volume":"400","author":"Feldman","year":"2022","journal-title":"Lancet"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.1016\/j.drudis.2019.03.015","article-title":"ADMET modeling approaches in drug discovery","volume":"24","author":"Ferreira","year":"2019","journal-title":"Drug Discov. Today"},{"key":"B15","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1517\/17460441.2015.1032936","article-title":"The MM\/PBSA and MM\/GBSA methods to estimate ligand-binding affinities","volume":"10","author":"Genheden","year":"2015","journal-title":"Expert Opin. Drug Discov."},{"key":"B16","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1186\/1758-2946-4-17","article-title":"Avogadro: an advanced semantic chemical editor, visualization, and analysis platform","volume":"4","author":"Hanwell","year":"2012","journal-title":"J. Cheminformatics"},{"key":"B17","doi-asserted-by":"publisher","first-page":"15451","DOI":"10.1038\/s41598-017-15571-7","article-title":"Protein-ligand blind docking using QuickVina-W with inter-process spatio-temporal integration","volume":"7","author":"Hassan","year":"2017","journal-title":"Sci. Rep."},{"key":"B18","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1001\/archneurol.2010.52","article-title":"Novel FUS\/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis","volume":"67","author":"Hewitt","year":"2010","journal-title":"Archives Neurology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1365","DOI":"10.3390\/diagnostics11081365","article-title":"Molecular pathology of ALS: what we currently know and what important information is still missing","volume":"11","author":"Jankovska","year":"2021","journal-title":"Diagnostics"},{"key":"B20","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1093\/bib\/2.2.195","article-title":"Swiss-PDB viewer (deep view)","volume":"2","author":"Kaplan","year":"2001","journal-title":"Briefings Bioinforma."},{"key":"B21","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.gene.2015.11.049","article-title":"Mutant SOD1 mediated pathogenesis of amyotrophic lateral sclerosis","volume":"577","author":"Kaur","year":"2016","journal-title":"Gene"},{"key":"B22","doi-asserted-by":"publisher","first-page":"10319","DOI":"10.1080\/07391102.2021.1942217","article-title":"Identification of plant-based hexokinase 2 inhibitors: combined molecular docking and dynamics simulation studies","volume":"40","author":"Khan","year":"2022","journal-title":"J. Biomol. Struct. Dyn."},{"key":"B23","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1093\/bioinformatics\/16.8.747","article-title":"PASS: prediction of activity spectra for biologically active substances","volume":"16","author":"Lagunin","year":"2000","journal-title":"Bioinformatics"},{"key":"B24","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/s1056-8719(00)00107-6","article-title":"Drug-like properties and the causes of poor solubility and poor permeability","volume":"44","author":"Lipinski","year":"2000","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"B25","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1038\/s41401-022-00972-w","article-title":"BL-918, a small-molecule activator of ULK1, induces cytoprotective autophagy for amyotrophic lateral sclerosis therapy","volume":"44","author":"Liu","year":"2023","journal-title":"Acta Pharmacol. Sin."},{"key":"B26","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1134\/s0026893308040195","article-title":"Radius of gyration as an indicator of protein structure compactness","volume":"42","author":"Lobanov","year":"2008","journal-title":"Mol. Biol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"9954","DOI":"10.1021\/jp003020w","article-title":"Structure and dynamics of the TIP3P, SPC, and SPC\/E water models at 298 K","volume":"105","author":"Mark","year":"2001","journal-title":"J. Phys. Chem. A"},{"key":"B28","doi-asserted-by":"publisher","first-page":"823","DOI":"10.3390\/molecules25040823","article-title":"Virtual screening approach to identify high-affinity inhibitors of serum and glucocorticoid-regulated kinase 1 among bioactive natural products: combined molecular docking and simulation studies","volume":"25","author":"Mohammad","year":"2020","journal-title":"Molecules"},{"key":"B29","doi-asserted-by":"publisher","first-page":"bbaa279","DOI":"10.1093\/bib\/bbaa279","article-title":"InstaDock: a single-click graphical user interface for molecular docking-based virtual high-throughput screening","volume":"22","author":"Mohammad","year":"2021","journal-title":"Briefings Bioinforma."},{"key":"B30","doi-asserted-by":"publisher","first-page":"W469","DOI":"10.1093\/nar\/gkae254","article-title":"Deep-PK: deep learning for small molecule pharmacokinetic and toxicity prediction","volume":"52","author":"Myung","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1362456","DOI":"10.3389\/fddsv.2024.1362456","article-title":"Integrative computational approaches for discovery and evaluation of lead compound for drug design","volume":"4","author":"Naithani","year":"2024","journal-title":"Front. Drug Discov."},{"key":"B32","doi-asserted-by":"publisher","first-page":"224108","DOI":"10.1063\/5.0004608","article-title":"The ORCA quantum chemistry program package","volume":"152","author":"Neese","year":"2020","journal-title":"J. Chem. Phys."},{"key":"B33","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1007\/s00401-017-1708-8","article-title":"Motor neuron vulnerability and resistance in amyotrophic lateral sclerosis","volume":"133","author":"Nijssen","year":"2017","journal-title":"Acta Neuropathol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.corsci.2015.01.037","article-title":"Density functional theory (DFT) as a powerful tool for designing new organic corrosion inhibitors. Part 1: an overview","volume":"99","author":"Obot","year":"2015","journal-title":"Corros. Sci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"2776","DOI":"10.1021\/acs.jmedchem.7b01575","article-title":"Small-molecule activator of UNC-51-like kinase 1 (ULK1) that induces cytoprotective autophagy for Parkinson\u2019s disease treatment","volume":"61","author":"Ouyang","year":"2018","journal-title":"J. Med. Chem."},{"key":"B36","doi-asserted-by":"publisher","first-page":"e00470","DOI":"10.1002\/prp2.470","article-title":"Pharmacokinetics and pharmacodynamics of a single dose nilotinib in individuals with parkinson's disease","volume":"7","author":"Pagan","year":"2019","journal-title":"Pharmacol. Res. Perspect."},{"key":"B37","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1093\/protein\/15.3.185","article-title":"Molecular dynamics simulations as a tool for improving protein stability","volume":"15","author":"Pikkemaat","year":"2002","journal-title":"Protein Eng."},{"key":"B38","doi-asserted-by":"publisher","first-page":"5327","DOI":"10.3390\/molecules26175327","article-title":"Therapeutic potential of natural products in treating neurodegenerative disorders and their future prospects and challenges","volume":"26","author":"Rahman","year":"2021","journal-title":"Molecules"},{"key":"B39","doi-asserted-by":"publisher","first-page":"263","DOI":"10.3389\/fnmol.2017.00263","article-title":"Autophagy dysregulation in ALS: when protein aggregates get out of hand","volume":"10","author":"Ramesh","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"B40","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1007\/s00415-025-12975-8","article-title":"Advancements in genetic research and RNA therapy strategies for amyotrophic lateral sclerosis (ALS): current progress and future prospects","volume":"272","author":"Ruffo","year":"2025","journal-title":"J. Neurology"},{"key":"B41","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1007\/978-1-4614-3912-7_4","article-title":"Phytochemistry of medicinal plants","volume":"1","author":"Saxena","year":"2013","journal-title":"J. Pharmacogn. Phytochemistry"},{"key":"B42","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1007\/s00249-011-0700-9","article-title":"Definition and testing of the GROMOS force-field versions 54A7 and 54B7","volume":"40","author":"Schmid","year":"2011","journal-title":"Eur. Biophysics J."},{"key":"B43","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1007\/978-981-15-6815-2_7","article-title":"Molecular dynamics simulation of protein and protein\u2013ligand complexes","author":"Shukla","year":"2020","journal-title":"Computer-aided Drug Des."},{"key":"B44","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1007\/978-981-15-8936-2_12","article-title":"Molecular dynamics simulation in drug discovery: opportunities and challenges","author":"Shukla","year":"2021","journal-title":"Innovations Implementations Comput. Aided Drug Discov. Strategies Ration. Drug Des."},{"key":"B45","doi-asserted-by":"publisher","first-page":"3541","DOI":"10.1080\/07391102.2017.1392897","article-title":"Identification of novel natural inhibitors of Opisthorchis felineus cytochrome P450 using structure-based screening and molecular dynamic simulation","volume":"36","author":"Shukla","year":"2018","journal-title":"J. Biomol. Struct. Dyn."},{"key":"B46","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/bs.apcsb.2023.11.003","article-title":"Computational resources and chemoinformatics for translational health research","volume":"139","author":"Tripathi","year":"2024","journal-title":"Adv. Protein Chem. Struct. Biol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1212","DOI":"10.4103\/1673-5374.300442","article-title":"ULK1 as a novel therapeutic target in neurodegeneration","volume":"16","author":"Vahsen","year":"2021","journal-title":"Neural Regen. Res."},{"key":"B48","doi-asserted-by":"publisher","first-page":"6281","DOI":"10.1021\/acs.jctc.1c00645","article-title":"gmx_MMPBSA: a new tool to perform end-state free energy calculations with GROMACS","volume":"17","author":"Vald\u00e9s-Tresanco","year":"2021","journal-title":"J. Chem. Theory Comput."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1701","DOI":"10.1002\/jcc.20291","article-title":"GROMACS: fast, flexible, and free","volume":"26","author":"Van Der Spoel","year":"2005","journal-title":"J. Comput. Chem."},{"article-title":"Discovery Studio Visualizer","year":"2005","author":"Visualizer","key":"B50"},{"key":"B51","doi-asserted-by":"publisher","first-page":"8827","DOI":"10.1021\/acsomega.3c00156","article-title":"IMPPAT 2.0: an enhanced and expanded phytochemical atlas of Indian medicinal plants","volume":"8","author":"Vivek-Ananth","year":"2023","journal-title":"ACS Omega"},{"key":"B52","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1002\/3527601813.ch6","article-title":"Hydrogen bonds in protein\u2010ligand complexes","author":"Williams","year":"2003","journal-title":"Protein-ligand Interact. Mol. Recognit. Drug Des."},{"key":"B53","doi-asserted-by":"publisher","first-page":"124","DOI":"10.4161\/auto.23323","article-title":"The ULK1 complex: sensing nutrient signals for autophagy activation","volume":"9","author":"Wong","year":"2013","journal-title":"Autophagy"},{"key":"B54","doi-asserted-by":"publisher","first-page":"944","DOI":"10.1007\/s00415-019-09652-y","article-title":"Global variation in prevalence and incidence of amyotrophic lateral sclerosis: a systematic review and meta-analysis","volume":"267","author":"Xu","year":"2020","journal-title":"J. Neurology"},{"key":"B55","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1089\/omi.2022.0044","article-title":"Death-associated protein kinase 3 inhibitors identified by virtual screening for drug discovery in cancer and hypertension","volume":"26","author":"Xue","year":"2022","journal-title":"OMICS"},{"key":"B56","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1093\/bioinformatics\/btp023","article-title":"Principal component analysis of native ensembles of biomolecular structures (PCA_NEST): insights into functional dynamics","volume":"25","author":"Yang","year":"2009","journal-title":"Bioinformatics"},{"key":"B57","doi-asserted-by":"publisher","first-page":"e1601167","DOI":"10.1126\/sciadv.1601167","article-title":"A C9ORF72\/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy","volume":"2","author":"Yang","year":"2016","journal-title":"Sci. Adv."},{"key":"B58","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1042\/EBC20170021","article-title":"The Mammalian ULK1 complex and autophagy initiation","volume":"61","author":"Zachari","year":"2017","journal-title":"Essays Biochem."},{"key":"B59","doi-asserted-by":"publisher","first-page":"2118","DOI":"10.1038\/s41598-017-02365-0","article-title":"CarcinoPred-EL: novel models for predicting the carcinogenicity of chemicals using molecular fingerprints and ensemble learning methods","volume":"7","author":"Zhang","year":"","journal-title":"Sci. Rep."},{"key":"B60","doi-asserted-by":"publisher","first-page":"2687","DOI":"10.1039\/c6sc05368h","article-title":"Discovery of a small molecule targeting ULK1-modulated cell death of triple negative breast cancer in vitro and in vivo","volume":"8","author":"Zhang","year":"","journal-title":"Chem. Sci."},{"key":"B61","doi-asserted-by":"publisher","first-page":"4239","DOI":"10.1021\/acs.jcim.9b00552","article-title":"Validation of the generalized force fields GAFF, CGenFF, OPLS-AA, and PRODRGFF by testing against experimental osmotic coefficient data for small drug-like molecules","volume":"59","author":"Zhu","year":"2019","journal-title":"J. Chem. Inf. Model."},{"key":"B62","doi-asserted-by":"publisher","first-page":"3743","DOI":"10.1016\/j.apsb.2022.06.004","article-title":"Autophagy and beyond: unraveling the complexity of UNC-51-like kinase 1 (ULK1) from biological functions to therapeutic implications","volume":"12","author":"Zou","year":"2022","journal-title":"Acta Pharm. Sin. B"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1661744\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T05:34:45Z","timestamp":1756964085000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1661744\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,4]]},"references-count":62,"alternative-id":["10.3389\/fphar.2025.1661744"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1661744","relation":{},"ISSN":["1663-9812"],"issn-type":[{"type":"electronic","value":"1663-9812"}],"subject":[],"published":{"date-parts":[[2025,9,4]]},"article-number":"1661744"}}