Identification of a druggable site on GRP78 at the GRP78-SARS-CoV-2 interface and virtual screening of compounds to disrupt that interface.
J Comput Aided Mol Des
; 38(1): 6, 2024 Jan 24.
Article
em En
| MEDLINE
| ID: mdl-38263499
ABSTRACT
SARS-CoV-2, the virus that causes COVID-19, led to a global health emergency that claimed the lives of millions. Despite the widespread availability of vaccines, the virus continues to exist in the population in an endemic state which allows for the continued emergence of new variants. Most of the current vaccines target the spike glycoprotein interface of SARS-CoV-2, creating a selection pressure favoring viral immune evasion. Antivirals targeting other molecular interactions of SARS-CoV-2 can help slow viral evolution by providing orthogonal selection pressures on the virus. GRP78 is a host auxiliary factor that mediates binding of the SARS-CoV-2 spike protein to human cellular ACE2, the primary pathway of cell infection. As GRP78 forms a ternary complex with SARS-CoV-2 spike protein and ACE2, disrupting the formation of this complex is expected to hinder viral entry into host cells. Here, we developed a model of the GRP78-Spike RBD-ACE2 complex. We then used that model together with hot spot mapping of the GRP78 structure to identify the putative binding site for spike protein on GRP78. Next, we performed structure-based virtual screening of known drug/candidate drug libraries to identify binders to GRP78 that are expected to disrupt spike protein binding to the GRP78, and thereby preventing viral entry to the host cell. A subset of these compounds has previously been shown to have some activity against SARS-CoV-2. The identified hits are starting points for the further development of novel SARS-CoV-2 therapeutics, potentially serving as proof-of-concept for GRP78 as a potential drug target for other viruses.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Vacinas
/
Glicoproteína da Espícula de Coronavírus
/
COVID-19
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Limite:
Humans
Idioma:
En
Revista:
J Comput Aided Mol Des
/
J. comput. aided mol. des
/
Journal of computer-aided molecular design
Assunto da revista:
BIOLOGIA MOLECULAR
/
ENGENHARIA BIOMEDICA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos