Discovery of novel checkpoint kinase 1 inhibitors by virtual screening based on multiple crystal structures

Yan Li, Dong Joon Kim, Wei-Ya Ma, Ronald A. Lubet, Ann M. Bode, Zigang Dong

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

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 60 000 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 IC50 value of 9.6 μM. 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.

Original languageEnglish (US)
Pages (from-to)2904-2914
Number of pages11
JournalJournal of Chemical Information and Modeling
Volume51
Issue number11
DOIs
StatePublished - Nov 28 2011

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