Design and synthesis of naturally-inspired SARS-CoV-2 inhibitors
Résumé
A naturally inspired chemical library of 25 molecules was synthesised guided by 3-D dimensionality and natural
product 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 of
molecular 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 cytotoxicity
difference. Computational analysis based on docking and molecular dynamics simulations against main protein
targets in SARS-CoV-2 (Main Protease Mpro, Nucleocapsid phosphoprotein, Non-structural protein nsp10/nsp16
complex and RBD/ACE2 complex) were performed. The computational analysis proposed the possible binding
targets 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 that
3b is targeting Mpro. These results open the way towards further hit-to-lead optimisations.
Domaines
Sciences du Vivant [q-bio]
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