Computational design of cancer drugs with SILCS

Computational design of PROTACs

PROTACs, or Proteolysis Targeting Chimeras, are molecules that combine two "warhead" ligands with a flexible linker, designed to increase the probability that the target protein (warhead 1) is degraded by an E3 Ubiquitin ligase (warhead 2), allowing the target protein's to be completely abolished. The PROTAC is catalytic and can have high activity despite transiently binding (due to covalent Ub labeling), enabling a much wider array of targets in principle than available to conventional noncovalent inhibitors. This project is ongoing in the MacKerell lab in Baltimore, MD, and is a part of my training in the Cancer Biology T32 in the Univ. Maryland Cancer Center. The approach will be to leverage the SILCS (GCMC/MD) fragment affinity FragMaps to determine the Target-Ligase Protein-Protein Interactions (PPIs) which can allow a PROTAC to bind, then determine which linkers bind best and presumably stablize the complex. We have constructed a large set of >20 protein-ligase complexes with >700 PROTACS characterized with various biological activity data to guide and benchmark our protocol.

Computational design of Covalent ligands for cancers like AML

Acute myeloid leukemia remains a challenging disease, due to drug resistant mutations that emerge rapidly in the clinic. In collaboration with Steve Fletcher and Curt Civin, we are developing a wide array of covalent ligands for targets involved in AML, such as the kinase FLT3 and the anti-apoptotic protein BFL-1. To learn more about the SILCS-Covalent method, you can read the paper of Yu, et al here.