Discovery of new binding elements in DPP-4 inhibition and their applications in novel DPP-4 inhibitor design

Gui-Bai Liang; Xiaoxia Qian; Tesfaye Biftu; Suresh Singh; Ying-Duo Gao; Giovanna Scapin; Sangita Patel; Barbara Leiting; Reshma Patel; Joseph Wu; Xiaoping Zhang; Nancy A Thornberry; Ann E Weber

doi:10.1016/j.bmcl.2008.05.061

Discovery of new binding elements in DPP-4 inhibition and their applications in novel DPP-4 inhibitor design

Bioorg Med Chem Lett. 2008 Jul 1;18(13):3706-10. doi: 10.1016/j.bmcl.2008.05.061. Epub 2008 May 20.

Authors

Gui-Bai Liang¹, Xiaoxia Qian, Tesfaye Biftu, Suresh Singh, Ying-Duo Gao, Giovanna Scapin, Sangita Patel, Barbara Leiting, Reshma Patel, Joseph Wu, Xiaoping Zhang, Nancy A Thornberry, Ann E Weber

Affiliation

¹ gui-bai_liang@merck.comMerck Research Laboratories, Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.

PMID: 18524582
DOI: 10.1016/j.bmcl.2008.05.061

Abstract

Probing with tool molecules, and by modeling and X-ray crystallography the binding modes of two structurally distinct series of DPP-4 inhibitors led to the discovery of a rare aromatic fluorine H-bond and the spatial requirement for better biaryl binding in the DPP-4 enzyme active site. These newly found binding elements were successfully incorporated into novel DPP-4 inhibitors.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Binding Sites
Chemistry, Pharmaceutical / methods
Crystallography, X-Ray / methods
Dipeptidyl Peptidase 4 / chemistry*
Dipeptidyl-Peptidase IV Inhibitors
Drug Design
Fluorine / chemistry
Glycine / chemistry
Humans
Hydrogen Bonding
Inhibitory Concentration 50
Models, Chemical
Models, Theoretical
Molecular Conformation
Software
beta-Alanine / chemistry

Substances

Dipeptidyl-Peptidase IV Inhibitors
beta-Alanine
Fluorine
DPP4 protein, human
Dipeptidyl Peptidase 4
Glycine