Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 21, Issue 22, Pages 6630-6635Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2011.09.093
Keywords
Molecular dynamics simulations; MM/GBSA; Aminomethylpyrimidine inhibitors; DPP-IV
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Funding
- National Science Foundation of China [21173264]
- Foundation of Knowledge Innovative Engineering of Chinese Academy of Sciences [ZNWH-2011-011]
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The aminomethylpyrimidines were investigated as a novel class of DPP-IV inhibitors. In this Letter, the binding mechanisms of how slight change of substitution or position influences the binding affinity of five representative analogs was investigated by molecular dynamics simulation, free energy calculations and energy decomposition analysis. The conserved hydrogen bonds with Glu205 and Glu206 slightly favor the inhibitor binding; the van der Waals interactions, especially the two key contacts with Tyr547 and Tyr666, dominate in the binding free energy and play a crucial role on distinguishing the high active inhibitors from the low ones. (C) 2011 Elsevier Ltd. All rights reserved.
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