J Chem Inf Model - Discovery of novel checkpoint kinase 1 inhibitors by virtual screening based on multiple crystal structures.

Tópicos

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Resumo

Incorporating receptor flexibility is considered crucial for improvement of docking-based virtual screening. With an abundance of crystallographic structures freely available, docking with multiple crystal structures is believed to be a practical approach to cope with protein flexibility. Here we describe a successful application of the docking of multiple structures to discover novel and potent Chk1 inhibitors. Forty-six Chk1 structures were first compared in single structure docking by predicting the binding mode and recovering known ligands. Combinations of different protein structures were then compared by recovery of known ligands and an optimal ensemble of Chk1 structures were selected. The chosen structures were used in the virtual screening of over 60000 diverse compounds for Chk1 inhibitors. Six novel compounds ranked at the top of the hits list were tested experimentally, and two of these compounds inhibited Chk1 activity-the best with an IC(50) value of 9.6 ?M. Further study indicated that achieving a better enrichment and identifying more diverse compounds was more likely using multiple structures than using only a single structure even when protein structures were randomly selected. Taking into account conformational energy difference did not help to improve enrichment in the top ranked list.

Resumo Limpo

incorpor receptor flexibl consid crucial improv dockingbas virtual screen abund crystallograph structur freeli avail dock multipl crystal structur believ practic approach cope protein flexibl describ success applic dock multipl structur discov novel potent chk inhibitor fortysix chk structur first compar singl structur dock predict bind mode recov known ligand combin differ protein structur compar recoveri known ligand optim ensembl chk structur select chosen structur use virtual screen divers compound chk inhibitor six novel compound rank top hit list test experiment two compound inhibit chk activityth best ic valu m studi indic achiev better enrich identifi divers compound like use multipl structur use singl structur even protein structur random select take account conform energi differ help improv enrich top rank list

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