Pharmacophore searches that include anchors, fragments
contributing above average to receptor binding, combined with
one-step syntheses are a powerful approach for the fast
discovery of novel bioactive molecules. Here, we are presenting
a pipeline for the rapid and efficient discovery of aspartyl
protease inhibitors. First, we hypothesized that hydrazine could
be a multi-valent warhead to interact with the active site Asp
carboxylic acids. We incorporated the hydrazine anchor in a
multicomponent reaction and created a large virtual library of
hydrazine derivatives synthetically accessible in one-step. Next,
we performed anchor-based pharmacophore screening of the
libraries and resynthesized top-ranked compounds. The inhibitory potency of the molecules was finally assessed by an
enzyme activity assay and the binding mode confirmed by
several soaked crystal structures supporting the validity of the
hypothesis and approach. The herein reported pipeline of tools
will be of general value for the rapid generation of receptor
binders beyond Asp proteases
