Modeling the binding affinities of beta-secretase inhibitors: application to subsite specificity

Ramkumar Rajamani; Charles H Reynolds

doi:10.1016/j.bmcl.2004.07.044

Modeling the binding affinities of beta-secretase inhibitors: application to subsite specificity

Bioorg Med Chem Lett. 2004 Oct 4;14(19):4843-6. doi: 10.1016/j.bmcl.2004.07.044.

Authors

Ramkumar Rajamani¹, Charles H Reynolds

Affiliation

¹ Johnson & Johnson Pharmaceutical Research and Development, Welsh and McKean Roads, PO Box 776, Spring House, PA 19477-0776, USA.

PMID: 15341936
DOI: 10.1016/j.bmcl.2004.07.044

Abstract

A new linear binding affinity model has been developed for hydroxyethylene based inhibitors of beta-secretase (BACE). This model is an improvement over a previously published model, and has been applied to a series of analogs not included in the training set. The linear model has been used to study subsite specificity for the P(2) through P(2)' positions, and to evaluate a small number of C-terminal analogs. The predicted rankings are in good agreement with experiment and support using this model for structure-based design of BACE inhibitors.

Publication types

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

MeSH terms

Amyloid Precursor Protein Secretases
Binding Sites
Drug Design
Endopeptidases / chemistry*
Endopeptidases / drug effects
Models, Molecular
Protease Inhibitors / chemistry
Protease Inhibitors / metabolism*
Structure-Activity Relationship

Substances

Protease Inhibitors
Amyloid Precursor Protein Secretases
Endopeptidases