J Chem Inf Model - Identification of sumoylation inhibitors targeting a predicted pocket in Ubc9.

Tópicos

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Resumo

Sumoylation is a post-translational modification that plays an important role in a wide range of cellular processes. Among the proteins involved in the sumoylation pathway, Ubc9 is the sole E2-conjugating enzyme required for sumoylation and plays a central role by interacting with almost all of the partners required for sumoylation. Ubc9 has been implicated in a variety of human malignancies. In order to exploit the therapeutic potential of Ubc9, we have identified the potential site to target for rational drug design using molecular modeling approaches. The structural information derived was then used to prioritize hits from a small-molecule library for biological assay using a virtual screening protocol that involves shape matching with a known inhibitor inhibitors and docking of a small-molecule library utilizing computational approaches that incorporate both ligand and protein flexibility. Nineteen compounds were acquired from different chemical vendors and were tested for Ubc9 inhibitory activity. Five compounds showed inhibitory activity against Ubc9, out of which one compound was selected for further optimization. A similarity search was then carried out to retrieve commercially available derivatives, which were further acquired and assayed, resulting in two compounds with acceptable potency. These two compounds can be used as starting points for the development of more potent inhibitors of Ubc9 targeting the predicted site.

Resumo Limpo

sumoyl posttransl modif play import role wide rang cellular process among protein involv sumoyl pathway ubc sole econjug enzym requir sumoyl play central role interact almost partner requir sumoyl ubc implic varieti human malign order exploit therapeut potenti ubc identifi potenti site target ration drug design use molecular model approach structur inform deriv use priorit hit smallmolecul librari biolog assay use virtual screen protocol involv shape match known inhibitor inhibitor dock smallmolecul librari util comput approach incorpor ligand protein flexibl nineteen compound acquir differ chemic vendor test ubc inhibitori activ five compound show inhibitori activ ubc one compound select optim similar search carri retriev commerci avail deriv acquir assay result two compound accept potenc two compound can use start point develop potent inhibitor ubc target predict site

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