The impact of ionization States of matrix metalloproteinase inhibitors on docking-based inhibitor design

Haizhen Zhong; Melissa A Wees; Theresa D Faure; Carol Carrillo; Jack Arbiser; J Phillip Bowen

doi:10.1021/ml200031m

The impact of ionization States of matrix metalloproteinase inhibitors on docking-based inhibitor design

ACS Med Chem Lett. 2011 Mar 29;2(6):455-60. doi: 10.1021/ml200031m. eCollection 2011 Jun 9.

Authors

Haizhen Zhong¹, Melissa A Wees¹, Theresa D Faure¹, Carol Carrillo², Jack Arbiser², J Phillip Bowen³

Affiliations

¹ Department of Chemistry, University of Nebraska at Omaha , DSC362, 6001 Dodge Street, Omaha, Nebraska 68182, United States.
² Department of Dermatology, School of Medicine, Emory University , Atlanta, Georgia 30322, United States.
³ Center for Drug Discovery, Department of Chemistry and Biochemistry, University of North Carolina at Greensboro , Greensboro, North Carolina 27402, United States ; Department of Nanoscience, Joint School of Nanoscience and Nanoengineering , 2901 East Lee Street, Suite 2200, Greensboro, North Carolina 27401, United States.

Abstract

The influence of ionization states of hydroxamates and retrohydroxamates and the presence of zinc ions in the active site were investigated using the wild-type and E402Q mutant of MMP-9. The deprotonated hydroxamates showed a significantly enhanced enrichment factor in the presence of zinc ions. A pharmacophore model was developed based on the deprotonated compounds and was used to identify four structurally diverse compounds with antiproliferative activities.

Keywords: Protonation state; and zinc binding group; chalcone; curcumin.