Drug leads for interactive protein targets with unknown structure

• We identify drug leads to disrupt associations of proteins with unknown structure.
• We describe a technology for drug discovery based on target protein sequence.
• We reveal a relation between binding hot spots and phosphorylation sites.
• It is possible to identify drug leads in the absence of target structure.

The disruption of protein–protein interfaces (PPIs) remains a challenge in drug discovery. The problem becomes daunting when the structure of the target protein is unknown and is even further complicated when the interface is susceptible to disruptive phosphorylation. Based solely on protein sequence and information about phosphorylation-susceptible sites within the PPI, a new technology has been developed to identify drug leads to inhibit protein associations. Here we reveal this technology and contrast it with current structure-based technologies for the generation of drug leads.The novel technology is illustrated by a patented invention to treat heart failure. The success of this technology shows that it is possible to generate drug leads in the absence of target structure.