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Discovery of Immunoproteasome Inhibitors Using Large-Scale Covalent Virtual Screening.

ABSTRACT: Large-scale virtual screening of boronic acid derivatives was performed to identify nonpeptidic covalent inhibitors of the ?5i subunit of the immunoproteasome. A hierarchical virtual screening cascade including noncovalent and covalent docking steps was applied to a virtual library of over 104,000 compounds. Then, 32 virtual hits were selected, out of which five were experimentally confirmed. Biophysical and biochemical tests showed micromolar binding affinity and time-dependent inhibitory potency for two compounds. These results validate the computational protocol that allows the screening of large compound collections. One of the lead-like boronic acid derivatives identified as a covalent immunoproteasome inhibitor is a suitable starting point for chemical optimization.

SUBMITTER: Scarpino A

PROVIDER: S-EPMC6680723 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Discovery of Immunoproteasome Inhibitors Using Large-Scale Covalent Virtual Screening.

Scarpino Andrea A Bajusz Dávid D Proj Matic M Gobec Martina M Sosič Izidor I Gobec Stanislav S Ferenczy György G GG Keserű György M GM

Molecules (Basel, Switzerland) 20190716 14

Large-scale virtual screening of boronic acid derivatives was performed to identify nonpeptidic covalent inhibitors of the β5i subunit of the immunoproteasome. A hierarchical virtual screening cascade including noncovalent and covalent docking steps was applied to a virtual library of over 104,000 compounds. Then, 32 virtual hits were selected, out of which five were experimentally confirmed. Biophysical and biochemical tests showed micromolar binding affinity and time-dependent inhibitory poten ...[more]

PMID: 31315311

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