{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T16:48:38Z","timestamp":1783529318518,"version":"3.55.0"},"reference-count":32,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,4,5]],"date-time":"2023-04-05T00:00:00Z","timestamp":1680652800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"King Khalid University","award":["RGP.2\/52\/1443"],"award-info":[{"award-number":["RGP.2\/52\/1443"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Alzheimer is a severe memory and cognitive impairment neurodegenerative disease that is the most common cause of dementia worldwide and characterized by the pathological accumulation of tau protein and amyloid-beta peptides. In this study, we have developed E-pharmacophore modeling to screen the eMolecules database with the help of a reported co-crystal structure bound with Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE-1). Flumemetamol, florbetaben, and florbetapir are currently approved drugs for use in the clinical diagnosis of Alzheimer\u2019s disease. Despite the benefits of commercially approved drugs, there is still a need for novel diagnostic agents with enhanced physicochemical and pharmacokinetic properties compared to those currently used in clinical practice and research. In the E-pharmacophore modeling results, it is revealed that two aromatic rings (R19, R20), one donor (D12), and one acceptor (A8) are obtained, and also that similar pharmacophoric features of compounds are identified from pharmacophore-based virtual screening. The identified screened hits were filtered for further analyses using structure-based virtual screening and MM\/GBSA. From the analyses, top hits such as ZINC39592220 and en1003sfl.46293 are selected based on their top docking scores (\u22128.182 and \u22127.184 Kcal\/mol, respectively) and binding free energy (\u221258.803 and \u221256.951 Kcal\/mol, respectively). Furthermore, a molecular dynamics simulation and MMPBSA study were performed, which revealed admirable stability and good binding free energy throughout the simulation period. Moreover, Qikprop results revealed that the selected, screened hits have good drug-likeness and pharmacokinetic properties. The screened hits ZINC39592220 and en1003sfl.46293 could be used to develop drug molecules against Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.3390\/life13040952","type":"journal-article","created":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T02:29:58Z","timestamp":1680748198000},"page":"952","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Identification of BACE-1 Inhibitors against Alzheimer\u2019s Disease through E-Pharmacophore-Based Virtual Screening and Molecular Dynamics Simulation Studies: An Insilco Approach"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7981-4562","authenticated-orcid":false,"given":"Kumarappan","family":"Chidambaram","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, Al-Qara Campus, King Khalid University, Asir Province, Abha 61421, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1006\/mcne.2000.0884","article-title":"ASP1 (BACE2) cleaves the amyloid precursor protein at the beta-secretase site","volume":"16","author":"Hussain","year":"2000","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1021\/acschemneuro.0c00719","article-title":"Viral Involvement in Alzheimer\u2019s Disease","volume":"12","author":"Sait","year":"2021","journal-title":"ACS Chem. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/S1474-4422(16)00062-4","article-title":"Defeating Alzheimer\u2019s disease and other dementias: A priority for European science and society","volume":"15","author":"Winblad","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s12276-019-0205-7","article-title":"Inhibition of \u03b2-site amyloid precursor protein cleaving enzyme 1 and cholinesterases by pterosins via a specific structure-activity relationship with a strong BBB permeability","volume":"51","author":"Jannat","year":"2019","journal-title":"Exp. Mol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.jep.2016.06.013","article-title":"BACE1 molecular docking and anti-Alzheimer\u2019s disease activities of ginsenosides","volume":"190","author":"Choi","year":"2016","journal-title":"J. Ethnopharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.3389\/fphar.2019.01355","article-title":"Therapeutic effects of natural drugs on Alzheimer\u2019s disease","volume":"10","author":"Ma","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"31","DOI":"10.3389\/fnagi.2016.00031","article-title":"Implications of GABAergic Neurotransmission in Alzheimer\u2019s Disease","volume":"8","author":"Li","year":"2016","journal-title":"Front. Aging Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2718","DOI":"10.1021\/acschemneuro.1c00206","article-title":"Evolving Role of Natural Products from Traditional Medicinal Herbs in the Treatment of Alzheimer\u2019s Disease","volume":"12","author":"Pandey","year":"2021","journal-title":"ACS Chem. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"21730","DOI":"10.1021\/jacs.0c09390","article-title":"Targeting microglia for therapy of Parkinson\u2019s disease by using biomimetic ultra-small nanoparticles","volume":"142","author":"Liu","year":"2020","journal-title":"J. Am. Chem. Soc."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"958453","DOI":"10.3389\/fphar.2022.958453","article-title":"Recognition of therapeutical potentials of Alchornea laxiflora (Benth.) Pax & K. Hoffm., an underexplored medicinal herb: A systematic review","volume":"13","author":"Jain","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"55","DOI":"10.4103\/0019-5545.44908","article-title":"Neurobiology of Alzheimer\u2019s disease","volume":"51","author":"Mohandas","year":"2009","journal-title":"Indian J. Psychiatry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"155","DOI":"10.3389\/fnagi.2019.00155","article-title":"Flavonoids as prospective neuroprotectants and their therapeutic propensity in aging associated neurological disorders","volume":"11","author":"Ayaz","year":"2019","journal-title":"Front. Aging Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1021\/jm901414e","article-title":"Design and synthesis of 5,5\u2019-disubstituted aminohydantoins as potent and selective human beta-secretase (BACE1) inhibitors","volume":"53","author":"Malamas","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"741703","DOI":"10.1155\/2014\/452625","article-title":"In silico design of BACE1 inhibitor for Alzheimer\u2019s disease by traditional Chinese medicine","volume":"2014","author":"Huang","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6765","DOI":"10.1039\/C3CS60460H","article-title":"BACE1 (\u03b2-secretase) inhibitors for the treatment of Alzheimer\u2019s disease","volume":"43","author":"Ghosh","year":"2014","journal-title":"Chem. Soc. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3687","DOI":"10.1080\/07391102.2017.1396255","article-title":"Ligand- and structure-based in silico studies to identify kinesin spindle protein (KSP) inhibitors as potential anticancer agents","volume":"36","author":"Balakumar","year":"2018","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4904","DOI":"10.1016\/j.ejmech.2010.07.063","article-title":"Synthesis, anti-inflammatory evaluation and docking studies of some new fluorinated fused quinazolines","volume":"45","author":"Balakumar","year":"2010","journal-title":"Eur. J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4314","DOI":"10.1080\/07391102.2020.1856184","article-title":"Atomistic simulation on flavonoids derivatives as potential inhibitors of bacterial gyrase of Staphylococcus aureus","volume":"40","author":"Ramachandran","year":"2020","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1080\/07391102.2020.1830855","article-title":"In silico approach of naringin as potent phosphatase and tensin homolog (PTEN) protein agonist against prostate cancer","volume":"40","author":"Muthumanickam","year":"2022","journal-title":"J. Biomol. Struct Dyn."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.jmgm.2013.08.009","article-title":"Design of e-pharmacophore models using compound fragments for the trans-sialidase of Trypanosoma cruzi: Screening for novel inhibitor scaffolds","volume":"45","author":"Miller","year":"2013","journal-title":"J. Mol. Graph. Model."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"558","DOI":"10.3109\/10799893.2016.1141955","article-title":"Inhibitor design against JNK1through e-pharmacophore modeling docking and molecular dynamics simulations","volume":"36","author":"Sudheer","year":"2016","journal-title":"J. Recept. Signal Transduct. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1002\/minf.201200169","article-title":"Multiple e-Pharmacophore modeling combined with high-throughput virtual screening and docking to identify potential inhibitors of \u03b2-secretase (BACE1)","volume":"32","author":"Palakurti","year":"2013","journal-title":"Mol. Inform."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1039\/C5MB00137D","article-title":"Identification of potential dual agonists of FXR and TGR5 using e-pharmacophore based virtual screening","volume":"11","author":"Sindhu","year":"2015","journal-title":"Mol. BioSyst."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"637122","DOI":"10.3389\/fmolb.2021.637122","article-title":"In silico screening of natural phytocompounds towards identification of potential lead compounds to treat COVID-19","volume":"8","author":"Sankar","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"637329","DOI":"10.3389\/fmolb.2021.637329","article-title":"Indian ethnomedicinal phytochemicals as promising inhibitors of rna-binding domain of SARS-CoV-2 nucleocapsid phosphoprotein: An in-silico study","volume":"8","author":"Muthumanickam","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1080\/07391102.2020.1715260","article-title":"Screening of inhibitors as potential remedial against Ebolavirus infection: Pharmacophore-based approach","volume":"39","author":"Muthumanickam","year":"2021","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"105144","DOI":"10.1016\/j.yrtph.2022.105144","article-title":"Standardization, in-silico and in-vivo safety assessment of methanol extract of Ziziphus mauritiana Lam leaves","volume":"131","author":"Ramar","year":"2022","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_28","first-page":"1916","article-title":"Curcumin-Celecoxib: A synergistic and rationale combination chemotherapy for breast cancer","volume":"25","author":"Alqahtani","year":"2021","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.1080\/07391102.2015.1111168","article-title":"E-pharmacophore filtering and molecular dynamics simulation studies in the discovery of potent drug-like molecules for chronic kidney disease","volume":"34","author":"Nagamani","year":"2016","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Liu, S., Fu, R., Cheng, X., Chen, S.P., and Zhou, L.H. (2012). Exploring the binding of BACE-1 inhibitors using comparative binding energy analysis (COMBINE). BMC Struct. Biol., 12.","DOI":"10.1186\/1472-6807-12-21"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"628585","DOI":"10.3389\/fmolb.2021.628585","article-title":"Prospective Role of Peptide-Based Antiviral Therapy Against the Main Protease of SARS-CoV-2","volume":"8","author":"Mahmud","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.ddtec.2004.11.007","article-title":"Lead- and drug-like compounds: The rule-of-five revolution","volume":"1","author":"Lipinski","year":"2004","journal-title":"Drug Discov. 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