{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:11:47Z","timestamp":1760127107332,"version":"build-2065373602"},"reference-count":40,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,5,7]],"date-time":"2023-05-07T00:00:00Z","timestamp":1683417600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Taif University Researchers Supporting Project","award":["TURSP-2020\/358"],"award-info":[{"award-number":["TURSP-2020\/358"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Replication of Human Cytomegalovirus (HCMV) requires the presence of a metal-dependent endonuclease at the C-terminus of pUL89, in order to properly pack and cleave the viral genome. Therefore, pUL89 is an attractive target to design anti-CMV intervention. Herein, we used integrated structure-based and ligand-based virtual screening approaches in combination with MD simulation for the identification of potential metal binding small molecule antagonist of pUL89. In this regard, the essential chemical features needed for the inhibition of pUL89 endonuclease domain were defined and used as a 3D query to search chemical compounds from ZINC and ChEMBL database. Thereafter, the molecular docking and ligand-based shape screening were used to narrow down the compounds based on previously identified pUL89 antagonists. The selected virtual hits were further subjected to MD simulation to determine the intrinsic and ligand-induced flexibility of pUL89. The predicted binding modes showed that the compounds reside well in the binding site of endonuclease domain by chelating with the metal ions and crucial residues. Taken in concert, the in silico investigation led to the identification of potential pUL89 antagonists. This study provided promising starting point for further in vitro and in vivo studies.<\/jats:p>","DOI":"10.3390\/molecules28093938","type":"journal-article","created":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T02:29:22Z","timestamp":1683512962000},"page":"3938","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Identification of Small Molecule Inhibitors of Human Cytomegalovirus pUL89 Endonuclease Using Integrated Computational Approaches"],"prefix":"10.3390","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7580-8667","authenticated-orcid":false,"given":"Mazen","family":"Almehmadi","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0806-6907","authenticated-orcid":false,"given":"Ihtisham Ul","family":"Haq","sequence":"additional","affiliation":[{"name":"Department of Physical Chemistry and Technology of Polymers, Silesian University of Technology, M. Strzody 9, 44-100 Gliwice, Poland"},{"name":"Joint Doctoral School, Silesian University of Technology, Akademicka 2A, 44-100 Gliwice, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4117-5811","authenticated-orcid":false,"given":"Ahad Amer","family":"Alsaiari","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5827-6040","authenticated-orcid":false,"given":"Fahad M.","family":"Alshabrmi","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Osama","family":"Abdulaziz","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7929-7748","authenticated-orcid":false,"given":"Mamdouh","family":"Allahyani","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammed","family":"Aladhadh","sequence":"additional","affiliation":[{"name":"Department of Food Science and Human Nutrition, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah 51452, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7116-3611","authenticated-orcid":false,"given":"Alaa","family":"Shafie","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdulelah","family":"Aljuaid","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rema Turki","family":"Alotaibi","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jawad","family":"Ullah","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Hazara University, Mansehra 21120, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nada Saud","family":"Alharthi","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e2034","DOI":"10.1002\/rmv.2034","article-title":"Estimation of the Worldwide Seroprevalence of Cytomegalovirus: A Systematic Review and Meta-Analysis","volume":"29","author":"Zuhair","year":"2019","journal-title":"Rev. Med. Virol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Ibrahim, S., Siddiqui, A.A., Siddiqui, A.R., Ahmed, W., Moss, P.A.H., and Lalani, E.-N.M.A. (2016). Sociodemographic Factors Associated with IgG and IgM Seroprevalence for Human Cytomegalovirus Infection in Adult Populations of Pakistan: A Seroprevalence Survey. BMC Public Health, 16.","DOI":"10.1186\/s12889-016-3772-8"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e01403","DOI":"10.1016\/j.idcr.2022.e01403","article-title":"Severe Cytomegalovirus Encephalitis in an Immunocompetent Healthy Young Woman: A Case Report","volume":"27","author":"Mozafarybazargany","year":"2022","journal-title":"IDCases"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Yurochko, A.D. (2021). Human Cytomegaloviruses: Methods and Protocols, Springer US. Methods in Molecular Biology.","DOI":"10.1007\/978-1-0716-1111-1"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e931821","DOI":"10.12659\/AJCR.931821","article-title":"Encephalitis Due to Co-Infection with Cytomegalovirus and Herpes Simplex Virus Type 2 in a Patient with Acquired Immunodeficiency Syndrome","volume":"22","author":"Zahid","year":"2021","journal-title":"Am. J. Case Rep."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Liu, X., Zhan, P., Men\u00e9ndez-Arias, L., and Poongavanam, V. (2021). Antiviral Drug Discovery and Development, Springer. Advances in Experimental Medicine and Biology.","DOI":"10.1007\/978-981-16-0267-2"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"104639","DOI":"10.1016\/j.antiviral.2019.104639","article-title":"Artemisone Demonstrates Synergistic Antiviral Activity in Combination with Approved and Experimental Drugs Active against Human Cytomegalovirus","volume":"172","author":"Laskov","year":"2019","journal-title":"Antivir. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1080\/14740338.2019.1662787","article-title":"Safety Considerations with Current and Emerging Antiviral Therapies for Cytomegalovirus Infection in Transplantation","volume":"18","author":"Razonable","year":"2019","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"105062","DOI":"10.1016\/j.antiviral.2021.105062","article-title":"The Antifungal Drug Isavuconazole Inhibits the Replication of Human Cytomegalovirus (HCMV) and Acts Synergistically with Anti-HCMV Drugs","volume":"189","author":"Mercorelli","year":"2021","journal-title":"Antivir. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1080\/13543784.2017.1274733","article-title":"Letermovir for the Management of Cytomegalovirus Infection","volume":"26","author":"Bowman","year":"2017","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1093\/jpids\/pit048","article-title":"Ganciclovir, Foscarnet, and Cidofovir: Antiviral Drugs Not Just for Cytomegalovirus","volume":"2","author":"Upadhyayula","year":"2013","journal-title":"J. Pediatr. Infect. Dis. Soc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"ofz375","DOI":"10.1093\/ofid\/ofz375","article-title":"Emergence and Persistence of Letermovir-Resistant Cytomegalovirus in a Patient With Primary Immunodeficiency","volume":"6","author":"Popping","year":"2019","journal-title":"Open Forum Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1093\/infdis\/jiaa462","article-title":"Drug Resistance Mutations and Associated Phenotypes Detected in Clinical Trials of Maribavir for Treatment of Cytomegalovirus Infection","volume":"226","author":"Chou","year":"2022","journal-title":"J. Infect. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"105326","DOI":"10.1016\/j.antiviral.2022.105326","article-title":"Cytomegalovirus Variation among Newborns Treated with Valganciclovir","volume":"203","author":"Dobbins","year":"2022","journal-title":"Antivir. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.chembiol.2005.12.002","article-title":"Selective Anti-Cytomegalovirus Compounds Discovered by Screening for Inhibitors of Subunit Interactions of the Viral Polymerase","volume":"13","author":"Loregian","year":"2006","journal-title":"Chem. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"8336","DOI":"10.1128\/JVI.77.15.8336-8344.2003","article-title":"Inhibition of Human Cytomegalovirus DNA Polymerase by C-Terminal Peptides from the UL54 Subunit","volume":"77","author":"Loregian","year":"2003","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1021\/acsinfecdis.1c00053","article-title":"Inhibition of Human Coronaviruses by Antimalarial Peroxides","volume":"7","author":"Ghosh","year":"2021","journal-title":"ACS Infect. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e202200334","DOI":"10.1002\/cmdc.202200334","article-title":"8-Hydroxy-1,6-Naphthyridine-7-Carboxamides as Inhibitors of Human Cytomegalovirus PUL89 Endonuclease","volume":"17","author":"Jung","year":"2022","journal-title":"ChemMedChem"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"106198","DOI":"10.1016\/j.bioorg.2022.106198","article-title":"Repurposing N-Hydroxy Thienopyrimidine-2,4-Diones (HtPD) as Inhibitors of Human Cytomegalovirus PUL89 Endonuclease: Synthesis and Biological Characterization","volume":"129","author":"He","year":"2022","journal-title":"Bioorg. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5830","DOI":"10.1021\/acs.jmedchem.2c00203","article-title":"4,5-Dihydroxypyrimidine Methyl Carboxylates, Carboxylic Acids, and Carboxamides as Inhibitors of Human Cytomegalovirus PUL89 Endonuclease","volume":"65","author":"He","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1016\/j.apsb.2021.08.019","article-title":"Discovery of N-Benzyl Hydroxypyridone Carboxamides as a Novel and Potent Antiviral Chemotype against Human Cytomegalovirus (HCMV)","volume":"12","author":"Senaweera","year":"2022","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.antiviral.2018.01.015","article-title":"Metal-Chelating 3-Hydroxypyrimidine-2,4-Diones Inhibit Human Cytomegalovirus PUL89 Endonuclease Activity and Virus Replication","volume":"152","author":"Wang","year":"2018","journal-title":"Antivir. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"113640","DOI":"10.1016\/j.ejmech.2021.113640","article-title":"Metal Binding 6-Arylthio-3-Hydroxypyrimidine-2,4-Diones Inhibited Human Cytomegalovirus by Targeting the PUL89 Endonuclease of the Terminase Complex","volume":"222","author":"Wang","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1093\/femsre\/fuy004","article-title":"The Human Cytomegalovirus Terminase Complex as an Antiviral Target: A Close-up View","volume":"42","author":"Ligat","year":"2018","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e02384-16","DOI":"10.1128\/JVI.02384-16","article-title":"Mutual Interplay between the Human Cytomegalovirus Terminase Subunits PUL51, PUL56, and PUL89 Promotes Terminase Complex Formation","volume":"91","author":"Neuber","year":"2017","journal-title":"J. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"16078","DOI":"10.1073\/pnas.1007144107","article-title":"Structure and Inhibition of Herpesvirus DNA Packaging Terminase Nuclease Domain","volume":"107","author":"Nadal","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e02152-16","DOI":"10.1128\/JVI.02152-16","article-title":"Inhibition of Human Cytomegalovirus PUL89 Terminase Subunit Blocks Virus Replication and Genome Cleavage","volume":"91","author":"Wang","year":"2017","journal-title":"J. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1002\/cmdc.201800283","article-title":"Hydroxypyridonecarboxylic Acids as Inhibitors of Human Cytomegalovirus PUL89 Endonuclease","volume":"13","author":"Kankanala","year":"2018","journal-title":"ChemMedChem"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8497","DOI":"10.1021\/acsomega.8b01472","article-title":"Structure-Driven Discovery of \u03b1,\u03b3-Diketoacid Inhibitors Against UL89 Herpesvirus Terminase","volume":"3","author":"Bongarzone","year":"2018","journal-title":"ACS Omega"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1002\/cmdc.200800129","article-title":"Integrating Structure- and Ligand-Based Virtual Screening: Comparison of Individual, Parallel, and Fused Molecular Docking and Similarity Search Calculations on Multiple Targets","volume":"3","author":"Tan","year":"2008","journal-title":"ChemMedChem"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1002\/cmdc.200900314","article-title":"Comparison of Structure- and Ligand-Based Virtual Screening Protocols Considering Hit List Complementarity and Enrichment Factors","volume":"5","author":"Evers","year":"2010","journal-title":"ChemMedChem"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1021\/ci2004835","article-title":"Virtual Screening Data Fusion Using Both Structure- and Ligand-Based Methods","volume":"52","author":"Svensson","year":"2012","journal-title":"J. Chem. Inf. Model."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Khan, S.A., Khan, A., Zia, K., Shawish, I., Barakat, A., and Ul-Haq, Z. (2022). Cheminformatics-Based Discovery of Potential Chemical Probe Inhibitors of Omicron Spike Protein. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231810315"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2607","DOI":"10.1080\/07391102.2020.1751298","article-title":"Identification of Chymotrypsin-like Protease Inhibitors of SARS-CoV-2 via Integrated Computational Approach","volume":"39","author":"Khan","year":"2021","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"129953","DOI":"10.1016\/j.molstruc.2021.129953","article-title":"Probing CAS Database as Prospective Antiviral Agents against SARS-CoV-2 Main Protease","volume":"1231","author":"Zia","year":"2021","journal-title":"J. Mol. Struct."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual Molecular Dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graph."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1021\/ci3001277","article-title":"ZINC: A Free Tool to Discover Chemistry for Biology","volume":"52","author":"Irwin","year":"2012","journal-title":"J. Chem. Inf. Model."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"D1100","DOI":"10.1093\/nar\/gkr777","article-title":"ChEMBL: A Large-Scale Bioactivity Database for Drug Discovery","volume":"40","author":"Gaulton","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1002\/jcc.20291","article-title":"GROMACS: Fast, Flexible, and Free","volume":"26","author":"Lindahl","year":"2005","journal-title":"J. Comput. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1021\/ci500020m","article-title":"G_mmpbsa\u2014A GROMACS Tool for High-Throughput MM-PBSA Calculations","volume":"54","author":"Kumari","year":"2014","journal-title":"J. Chem. Inf. Model."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/9\/3938\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:30:49Z","timestamp":1760124649000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/9\/3938"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,7]]},"references-count":40,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["molecules28093938"],"URL":"https:\/\/doi.org\/10.3390\/molecules28093938","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2023,5,7]]}}}