Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein

TY - JOUR

T1 - Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein

AU - Deganutti, Giuseppe

AU - Prischi, Filippo

AU - Reynolds, Christopher A.

N1 - Funding Information: CAR and GD received funding from Leverhulme Trust Grant No. RPG-2017-255. Publisher Copyright: © 2020, Springer Nature Switzerland AG.

PY - 2021/2

Y1 - 2021/2

N2 - The recent outbreak of the respiratory syndrome-related coronavirus (SARS-CoV-2) is stimulating an unprecedented scientific campaign to alleviate the burden of the coronavirus disease (COVID-19). One line of research has focused on targeting SARS-CoV-2 proteins fundamental for its replication by repurposing drugs approved for other diseases. The first interaction between the virus and the host cell is mediated by the spike protein on the virus surface and the human angiotensin-converting enzyme (ACE2). Small molecules able to bind the receptor-binding domain (RBD) of the spike protein and disrupt the binding to ACE2 would offer an important tool for slowing, or even preventing, the infection. Here, we screened 2421 approved small molecules in silico and validated the docking outcomes through extensive molecular dynamics simulations. Out of six drugs characterized as putative RBD binders, the cephalosporin antibiotic cefsulodin was further assessed for its effect on the binding between the RBD and ACE2, suggesting that it is important to consider the dynamic formation of the heterodimer between RBD and ACE2 when judging any potential candidate.

AB - The recent outbreak of the respiratory syndrome-related coronavirus (SARS-CoV-2) is stimulating an unprecedented scientific campaign to alleviate the burden of the coronavirus disease (COVID-19). One line of research has focused on targeting SARS-CoV-2 proteins fundamental for its replication by repurposing drugs approved for other diseases. The first interaction between the virus and the host cell is mediated by the spike protein on the virus surface and the human angiotensin-converting enzyme (ACE2). Small molecules able to bind the receptor-binding domain (RBD) of the spike protein and disrupt the binding to ACE2 would offer an important tool for slowing, or even preventing, the infection. Here, we screened 2421 approved small molecules in silico and validated the docking outcomes through extensive molecular dynamics simulations. Out of six drugs characterized as putative RBD binders, the cephalosporin antibiotic cefsulodin was further assessed for its effect on the binding between the RBD and ACE2, suggesting that it is important to consider the dynamic formation of the heterodimer between RBD and ACE2 when judging any potential candidate.

KW - COVID-19

KW - Drug repurposing

KW - Molecular dynamics

KW - SARS-CoV-2

KW - Spike protein

KW - Supervised molecular dynamics

UR - http://www.scopus.com/inward/record.url?scp=85093670962&partnerID=8YFLogxK

U2 - 10.1007/s10822-020-00356-4

DO - 10.1007/s10822-020-00356-4

M3 - Article

C2 - 33103220

AN - SCOPUS:85093670962

SN - 0920-654X

VL - 35

SP - 195

EP - 207

JO - Journal of Computer-Aided Molecular Design

JF - Journal of Computer-Aided Molecular Design

IS - 2

ER -