A rigorous computational screening protocol was applied to identify novel fragment-like inhibitors of N5-CAIR mutase (PurE), a key enzyme involved in de novo purine synthesis that represents a novel target for antibacterial drug design. This computational screening protocol utilized molecular docking, GPU-accelerated molecular dynamics and MM/PBSA free energy estimations to investigate the binding modes and energies of fragments in the active site of PurE. PurE is a functional octamer comprised of identical subunits. The octameric structure, with its eight active sites, provided a distinct advantage in these studies. This is because, for a given simulation length, we were able to place eight separate fragment compounds in the active sites to increase the throughput of the MM/PBSA analysis.  We screened our in-house library which consists of 352 fragments. To validate, the top ranking fragments' binding affinities were compared with experimental data. Supported in part by Defense Threat Reduction Agency Contract HDTRA1-11-C-0011.

Fragment-based lead discovery using a multi-domain, parallel MM/PBSA simulation screening protocol

243rd National Meeting (2012)

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