Targeting the RNA-Binding Site of SARS-CoV-2 NSP13 by FRASE-bot in CACHE Challenge #2.

The Critical Assessment of Computational Hit-Finding Experiments (CACHE) Challenges came forward as real-world stress tests for virtual screening methods. In Challenge #2, the focus was on SARS-CoV-2 NSP13 helicase─the most conserved protein across Coronaviridae and a prime target for broad-spectrum antivirals. We brought in FRASE-based hit-finding robot (FRASE-bot), our fragment-based screening engine that delimits target-relevant chemical space and identifies likely binding sites. Guided by FRASE-bot, 79 compounds were selected over two rounds. Round 1 delivered four confirmed binders of NSP13 with dissociation constants between 11 and 61 μM. Round 2 pushed further: five analogs bound in the micromolar range, with compounds 8 and 9 (derived from the parent hit 2) showing clear gains over other CACHE participants. With successful runs in both CACHE #1 and #2, FRASE-bot is proving its ability to tackle tough protein targets. The identification of validated binders targeting the RNA-binding groove of SARS-CoV-2 NSP13 holds significant promise for antiviral drug discovery.