Software for Fragment-based Design of Covalent Inhibitors

DESCRIPTION (provided by applicant): Covalent drugs represent a significant portion of current pharmaceuticals, with the top 26 having sales of over 30B in the US alone. While in the past target-directed drug discovery projects rarely pursued covalent binders due to safety concerns, the industry is increasingly considering the use of targeted covalent inhibitors (TCIs) that utilize soft reactive warheads, weak electrophiles that become locally reactive only in the context of the topology of a binding site.Developing a TCI requires a potent and specific reversible scaffold and the ability to covalently bind it to a selective group, most frequently a cysteine side chain. Tools exist for the design of covalent inhibitors starting from known reversible inhibitors, but for many targets there are no appropriate starting compounds. The general goal of this Phase I SBIR proposal is to develop algorithms and software for the efficient design of covalent inhibitors that will be based on well-established principl