Star-shaped Triazine-derivatives: would they crossbind SARS-CoV-2 spike helices?

Abstract

This work describes synthesizable water-soluble Triazine-derivatives computationally crossbinding the S spike helices of Severe Acute Respiratory Syndrome coronavirus (SARS)-CoV-2. The "spring-loaded switch-folding” (S-SLSF) α-helices included in the S homotrimer top-to-bottom cavity and implicated in viral-host membrane fusion were targeted by star-shaped Trihydroxyl-Triphenyl-Triazines (TTT) leads at subnanomolar binding-scores. Exploration of in silico leads among millions of molecular candidates, included several similar searches, core-replacement, fragment extensions, or convolutional neural network deep-screening combined with hundreds of water-soluble lead-derivatives identified by manual iterations and commercially available building-blocks for chemical synthesis. The lead-derivatives are briefly discussed for in vitro validation and possibilities of fusion inhibition substituting mutations.