Denovo designing, retrosynthetic analysis, and combinatorial synthesis of a hybrid antiviral (VTAR-01) to inhibit the interaction of SARS-CoV2 spike glycoprotein with human angiotensin-converting enzyme 2.

Tiwari, Vishvanath

SARS-like coronavirus (SARS-CoV2) has emerged as a global threat to humankind and is rapidly spreading. The infectivity, pathogenesis, and infection of this virus are dependent on the interaction of SARS-CoV2 spike protein with human ACE2 (hACE2). Spike protein contains a receptor-binding domain (RBD) that recognizes hACE-2. In the present study, we are reporting a denovo designed novel hybrid antiviral 'VT-AR-01' molecule that binds at the interface of RBD-hACE2 interaction. A series of antiviral molecules were tested for binding at the interface of RBD-hACE2 interaction. In-silico screening, molecular mechanics, molecular dynamics simulation (MDS) analysis suggest ribavirin, ascorbate, lopinavir, and hydroxychloroquine have strong interaction at RBD-hACE2 interface. These four molecules were used for denovo fragment-based antiviral design. Denovo designing, docking, and MDS analysis identified a 'VTAR' hybrid molecule that has better interaction with this interface as compared to all antiviral used to design it. We have further used retrosynthetic analysis and combinatorial synthesis to design 100 variants of VT-AR molecules. Retrosynthetic analysis and combinatorial synthesis, along with docking and MDS, identified VT-AR-01 that interact with the interface of the RBD-ACE2 complex. MDS analysis confirmed its interaction with the RBD-ACE2 interface by involving Glu35 and Lys353 of ACE2, as well as Gln493 and Ser494 of RBD. Interaction of spike protein with ACE2 is essential for pathogenesis and infection of this virus; hence, this in-silico designed hybrid antiviral molecule (VT-AR-01) that binds at the interface of RBD-hACE2 may be further developed to control the infection of SARS-CoV2.