0 avis
Design and synthesis of naturally-inspired SARS-CoV-2 inhibitors
Archive ouverte
Edité par CCSD ; Royal Society of Chemistry -
International audience. A naturally inspired chemical library of 25 molecules was synthesised guided by 3-D dimensionality and naturalproduct likeness factors to explore a new chemical space. The synthesised chemical library, consisting of fused-bridged dodecahydro-2a,6-epoxyazepino[3,4,5-cd] indole skeletons, followed lead likeness factors in terms ofmolecular weight, C-sp3 fraction and CLogP. Screening of the 25 compounds against lung cells infected with SARS-CoV-2 led to the identification of 2 hits. Although the chemical library showed cytotoxicity, the two hits (3b, 9e)showed the highest antiviral activity (EC50 values of 3.7 and 1.4 μM, respectively) with acceptable cytotoxicitydifference. Computational analysis based on docking and molecular dynamics simulations against main proteintargets in SARS-CoV-2 (Main Protease Mpro, Nucleocapsid phosphoprotein, Non-structural protein nsp10/nsp16complex and RBD/ACE2 complex) were performed. The computational analysis proposed the possible bindingtargets to be either Mpro or nsp10/nsp16 complex. Biological assasys were performed to confirm this propostion.A cell-based assay for Mpro protease activity using a Reverse-Nanoluciferase (Rev-Nluc) reporter confirmed that3b is targeting Mpro. These results open the way towards further hit-to-lead optimisations.
Consulter en ligne
Suggestions
Du même auteur
