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Bioorg Med Chem. 2012 Jul 15;20(14):4462-71. doi: 10.1016/j.bmc.2012.05.029. Epub 2012 May 19.

Furin inhibitors: importance of the positive formal charge and beyond.

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  • 1Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA.

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  • Bioorg Med Chem. 2012 Oct 15;20(20):6195-7.

Abstract

Furin is the prototype member of the proprotein convertases superfamily. Proprotein convertases are associated with hormonal response, neural degeneration, viral and bacterial activation, and cancer. Several studies over the last decade have examined small molecules, natural products, peptides and peptide derivatives as furin inhibitors. Currently, subnanomolar inhibition of furin is possible. Herein, we report the analysis of 115 furin inhibitors reported in the literature. Analysis of the physicochemical properties of these compounds highlights the dependence of the inhibitory potency with the total formal charge and also shows how the most potent (peptide-based) furin inhibitors have physicochemical properties similar to drugs. In addition, we report docking studies of 26 furin inhibitors using Glide XP. Inspection of binding interactions shows that the two putative binding modes derived from our study are reasonable. Analysis of the binding modes and protein-ligand interaction fingerprints, used here as postdocking procedure, shows that electrostatic interactions predominate on S1, S2 and S4 subsites but are seldom in S3. Our models also show that the benzimidamide group, present in the most active inhibitors, can be accommodated in the S1 subsite. These results are valuable for the design of new furin inhibitors.

Copyright © 2012 Elsevier Ltd. All rights reserved.

PMID:
22682919
[PubMed - indexed for MEDLINE]

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