Star-shaped molecules cross-bind to SARS-CoV2 spike α-helices in silico

Despite docking to the isolated α-helix residues 960-1010 (“spring-loaded switch-folding”, SLSF) of wild-type S spike trimers of Severe Acute Respiratory Syndrome coronavirus (SARS)-CoV2, the star-shaped hydrophobic Tinosorb failed to dock to SLSF inside the S (S-SLSF) and to inhibit viral-host cell membrane fusion1. This work discovered computational star-shaped-similar molecules exhibiting lower binding-scores (higher-affinities) to S-SLSF with probable cross-binding properties of their targeted α-helices but with lower hydrophobicities and smaller molecular sizes. Most star-shaped-similar leads contained Trihydroxyl-Triphenyls arms branching from each of the three carbons of a central Triazine core (TTT). Deconstruction of TTTs by core-replacement (X), fragment extension (F), and 2D deep-screening among millions of molecular possibilities, found additional leads that by combining structural features (F+TTX) reduced their binding-scores to S-SLSF. Such leads maximize their possibilities to stabilize wild-type S-SLSF α-helices, with the aim to reduce host-coronavirus membrane fusion using drug-like ligands rather than mutations.