A computational approach to drug repurposing against SARS-CoV-2 RNA dependent RNA polymerase (RdRp)

Abstract

The spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) caused a worldwide outbreak of coronavirus disease 19 (COVID-19), which rapidly evolved as a global concern. The efforts of the scientific community are pointed towards the identification of promptly available therapeutic options. RNA-dependent RNA polymerase (RdRp) is a promising target for developing small molecules to contrast SARS-CoV-2 replication. Modern computational tools can boost identification and repurposing of known drugs targeting RdRp. We here report the results regarding the screening of a database containing more than 8800 molecules, including approved, experimental, nutraceutical, illicit, withdrawn and investigational compounds. The molecules were docked against the cryo-electron microscopy structure of SARS-CoV-2 RdRp, optimized by means of molecular dynamics (MD) simulations. The adopted three-stage ensemble docking study underline that compounds formerly developed as kinase inhibitors may interact with RdRp.

Insight into the LFA-1/SARS-CoV-2 Orf7a Complex by Protein–Protein Docking, Molecular Dynamics, and MM-GBSA Calculations

“…The frames composing the MD trajectory obtained for the protein–protein complexes were analyzed with the Prime MM-GBSA tool included in the Schrödinger suite, as reported in a previous work. 38 In greater detail, starting after system stabilization, one in every 400 frames (one every 3.7 ns) was considered for a total of 27 frames for each simulation. The complexes were refined with Prime under the OPLS3e force field adopting the Variable Dielectric Surface Generalized Born (VSGB) continuum solvation model.…”

A Drug Repurposing Approach for Antimalarials Interfering with SARS-CoV-2 Spike Protein Receptor Binding Domain (RBD) and Human Angiotensin-Converting Enzyme 2 (ACE2)

“…In this connection, several of these targets are under examination [11][12][13]. The screening of drugs approved by the FDA for other purposes is an attractive strategy [14], as this has the potential of providing expedited treatment of SARS-CoV-2 infection [9,15,16]. Specifically, targeting the ACE2-RBD assembly with low molecular weight drugs [17,18] and identifying other small molecules interfering with this recognition mechanism will prevent cell invasion by the virus, and thereby block infection [19].…”

A COVID-19 Drug Repurposing Strategy through Quantitative Homological Similarities Using a Topological Data Analysis-Based Framework

“…Lastly, the RNA-dependent RNA polymerase nsp12 of SARS-CoV-2 is a protein that performs essential functions in the coronavirus life cycle with no host cell homolog. This is an advantage for antiviral drug development, reducing the risk of affecting any protein present in human cells, as has been proven by many drug repurposing studies directed against nsp12 RdRP [ 57 , 58 , 59 , 60 ]. Vemurafenib, sorafenib, and raloxifene may be potential candidates against nsp12 RdRP.…”