Laboratory for Structural Bioinformatics

SUMO activating enzyme 1 (SUMO E1) is responsible for the activation of SUMO in the first step of the sumoylation cascade. SUMO E1 is linked to many human diseases including cancer and thus making it a potential therapeutic target. There are few reported SUMO E1 inhibitors including several natural products. To identify small molecule inhibitors of SUMO E1 with better drug-like properties for potential therapeutic studies, we have used structure based virtual screening to identify hits from Maybridge small molecule library for biological assay. Our virtual screening protocol involves the fast docking of the entire small molecule library with rigid protein and ligands followed by redocking of top hits using a method that incorporates both ligand and protein flexibility. Subsequently, the top ranking compounds were prioritized using molecular dynamics simulation based binding free energy calculation. Out of 24 compounds that were acquired and tested using in vitro sumoylation assay, four of them showed more than 85% inhibition of sumoylation with the most active compound showed an IC50 of 14.4 μM. A similarity search with the most active compound in the ZINC database has identified three more compounds with improved potency. These compounds share a common phenyl urea scaffold and have been confirmed to inhibit SUMO E1 by in vitro SUMO-1 thioester bond formation assay. Our study suggests that these phenyl urea compounds could be used as a starting point for the development of novel therapeutic agents. This project is a collaboration with Dr. Minoru Yoshida, Chemical Genetics Laboratory, RIKEN. This work has been published in JCIM (publication).
We have also identified quinazolinyloxy biaryl urea as a new class of SUMO E1 inhibitors in collaboration with Dr. Minoru Yoshida, Chemical Genetics Laboratory, RIKEN. The most active compound of this class inhibited the in vitro sumoylation with an IC50 of 13.4 μM. This compound inhibits sumoylation by blocking the formation of SUMO-E1 thioester intermediate. The biological activity of the most active compound is comparable to previously reported inhibitors with properties suitable for medicinal chemistry optimization for potency and druggability. This work has been published in BMCL (publication). We have recently identified pyrazole and thiazole urea containing compounds as new classes of SUMO E1 inhibitors in collaboration with Dr. Minoru Yoshida, Chemical Genetics Laboratory, RIKEN. We have utilized 3D-shape matching, electrostatic potential similarity evaluations and molecular docking to scaffold hop from a previously known aryl urea scaffold. This work has been published in BMCL (publication).