J Chem Inf Model - Identification of sumoylation activating enzyme 1 inhibitors by structure-based virtual screening.

Tópicos

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{ use(1733) differ(960) four(931) }
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Resumo

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, 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 the Maybridge small molecule library for biological assay. Our virtual screening protocol involves 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 the 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 showing an IC50 of 14.4 ?M. 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.

Resumo Limpo

sumo activ enzym sumo e respons activ sumo first step sumoyl cascad sumo e link mani human diseas includ cancer thus make potenti therapeut target report sumo e inhibitor includ sever natur product identifi small molecul inhibitor sumo e better druglik properti potenti therapeut studi use structurebas virtual screen identifi hit maybridg small molecul librari biolog assay virtual screen protocol involv fast dock entir small molecul librari rigid protein ligand follow redock top hit use method incorpor ligand protein flexibl subsequ toprank compound priorit use molecular dynam simulationbas bind free energi calcul compound acquir test use vitro sumoyl assay four show inhibit sumoyl activ compound show ic m similar search activ compound zinc databas identifi three compound improv potenc compound share common phenyl urea scaffold confirm inhibit sumo e vitro sumo thioester bond format assay studi suggest phenyl urea compound use start point develop novel therapeut agent

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