Identification of small molecule inhibitors of the Chloracidobacterium thermophilum type IV pilus protein PilB by ensemble virtual screening

Simple item page
dc.contributor.authorMcDonald-Ramos, Jay S.en
dc.contributor.authorHicklin, Ian K.en
dc.contributor.authorYang, Zhaominen
dc.contributor.authorBrown, Anne M.en
dc.date.accessioned2025-01-22T14:00:58Zen
dc.date.available2025-01-22T14:00:58Zen
dc.date.issued2024-08-16en
dc.description.abstractAntivirulence strategy has been explored as an alternative to traditional antibiotic development. The bacterial type IV pilus is a virulence factor involved in host invasion and colonization in many antibiotic resistant pathogens. The PilB ATPase hydrolyzes ATP to drive the assembly of the pilus filament from pilin subunits. We evaluated Chloracidobacterium thermophilum PilB (CtPilB) as a model for structure-based virtual screening by molecular docking and molecular dynamics (MD) simulations. A hexameric structure of CtPilB was generated through homology modeling based on an existing crystal structure of a PilB from Geobacter metallireducens. Four representative structures were obtained from molecular dynamics simulations to examine the conformational plasticity of PilB and improve docking analyses by ensemble docking. Structural analyses after 1 μs of simulation revealed conformational changes in individual PilB subunits are dependent on ligand presence. Further, ensemble virtual screening of a library of 4234 compounds retrieved from the ZINC15 database identified five promising PilB inhibitors. Molecular docking and binding analyses using the four representative structures from MD simulations revealed that top-ranked compounds interact with multiple Walker A residues, one Asp-box residue, and one arginine finger, indicating these are key residues in inhibitor binding within the ATP binding pocket. The use of multiple conformations in molecular screening can provide greater insight into compound flexibility within receptor sites and better inform future drug development for therapeutics targeting the type IV pilus assembly ATPase.en
dc.description.versionPublished versionen
dc.format.extent12 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifierARTN 110127 (Article number)en
dc.identifier.doihttps://doi.org/10.1016/j.abb.2024.110127en
dc.identifier.eissn1096-0384en
dc.identifier.issn0003-9861en
dc.identifier.orcidYang, Zhaomin [0000-0002-2044-6793]en
dc.identifier.orcidBrown, Anne [0000-0001-6951-8228]en
dc.identifier.otherS0003-9861(24)00249-2 (PII)en
dc.identifier.pmid39154818en
dc.identifier.urihttps://hdl.handle.net/10919/124300en
dc.identifier.volume760en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/39154818en
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectAntivirulenceen
dc.subjectVirtual screeningen
dc.subjectMolecular dynamicsen
dc.subjectMolecular dockingen
dc.subjectBacterial type 4 pilusen
dc.subject.meshFimbriae, Bacterialen
dc.subject.meshOxidoreductasesen
dc.subject.meshBacterial Proteinsen
dc.subject.meshAnti-Bacterial Agentsen
dc.subject.meshDrug Evaluation, Preclinicalen
dc.subject.meshAmino Acid Sequenceen
dc.subject.meshSmall Molecule Librariesen
dc.subject.meshMolecular Dynamics Simulationen
dc.subject.meshAcidobacteriaen
dc.subject.meshMolecular Docking Simulationen
dc.titleIdentification of small molecule inhibitors of the<i> Chloracidobacterium</i><i> thermophilum</i> type IV pilus protein PilB by ensemble virtual screeningen
dc.title.serialArchives of Biochemistry and Biophysicsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
dcterms.dateAccepted2024-08-15en
pubs.organisational-groupVirginia Techen
pubs.organisational-groupVirginia Tech/Scienceen
pubs.organisational-groupVirginia Tech/Science/Biological Sciencesen
pubs.organisational-groupVirginia Tech/Libraryen
pubs.organisational-groupVirginia Tech/Faculty of Health Sciencesen
pubs.organisational-groupVirginia Tech/All T&R Facultyen
pubs.organisational-groupVirginia Tech/Science/COS T&R Facultyen
pubs.organisational-groupVirginia Tech/Library/Research, Learning, and Informaticsen
pubs.organisational-groupVirginia Tech/Library/Research, Learning, and Informatics/Data Servicesen

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
Published-Jay.pdf
Size:
8.65 MB
Format:
Adobe Portable Document Format
Description:
Published version
Download
License bundle
Now showing 1 - 1 of 1
Name:
license.txt
Size:
1.5 KB
Format:
Plain Text
Description:
Download

Collections

All Faculty Deposits
Scholarly Works, Biochemistry
Scholarly Works, Biological Sciences
Scholarly Works, Center for Emerging, Zoonotic, and Arthropod-borne Pathogens (CeZAP)
Scholarly Works, University Libraries
Scholarly Works, Virginia Tech Center for Drug Discovery