J Chem Inf Model - Validation of the AmpC ?-lactamase binding site and identification of inhibitors with novel scaffolds.

Tópicos

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Resumo

AmpC ?-lactamase confers resistance to ?-lactam antibiotics in multiple Gram-negative bacteria. Therefore, identification of non-?-lactam compounds that inhibit the enzyme is considered crucial to the development of novel antibacterial therapies. Given the highly solvent-exposed active site, it is important to study the induced-fit movements and water-mediated interactions to improve docking accuracy and virtual screening enrichments in structure-based design of new AmpC inhibitors. Here, we tested multiple models of the AmpC binding site to investigate the importance of conserved water molecules and binding site plasticity on molecular docking. The results indicate that at least one conserved water molecule greatly improves the binding pose predictions and virtual screening enrichments of known noncovalent AmpC inhibitors. The best model was tested prospectively in the virtual screening of about 6 million commercially available compounds. Sixty-one chemically diverse top-scoring compounds were experimentally tested, which led to the identification of seven previously unknown inhibitors. These findings validate the essential features of the AmpC binding site for molecular recognition and are useful for further optimization of identified inhibitors.

Resumo Limpo

ampc lactamas confer resist lactam antibiot multipl gramneg bacteria therefor identif nonlactam compound inhibit enzym consid crucial develop novel antibacteri therapi given high solventexpos activ site import studi inducedfit movement watermedi interact improv dock accuraci virtual screen enrich structurebas design new ampc inhibitor test multipl model ampc bind site investig import conserv water molecul bind site plastic molecular dock result indic least one conserv water molecul great improv bind pose predict virtual screen enrich known noncoval ampc inhibitor best model test prospect virtual screen million commerci avail compound sixtyon chemic divers topscor compound experiment test led identif seven previous unknown inhibitor find valid essenti featur ampc bind site molecular recognit use optim identifi inhibitor

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