Prev. Article Next Article Table of Contents

Letter

Interpreting Steep Dose-Response Curves in Early Inhibitor Discovery

Brian K. Shoichet^†

Department of Pharmaceutical Chemistry, University of CaliforniaSan Francisco, 1700 4th Street, San Francisco, California 94158

J. Med. Chem., 2006, 49 (25), pp 7274–7277

DOI: 10.1021/jm061103g

Publication Date (Web): November 10, 2006

†

Phone: 415-514-4126. Fax: 415-514-4260. E-mail: shoichet@ cgl.ucsf.edu.

Abstract

Many screening hits inhibit enzymes with steep dose-response curves, which are considered pathological. Three models might explain these curves: multisite binding, an inhibitor phase transition, or stoichiometric inhibition caused by a high enzyme to K_d ratio. Experiments with promiscuous aggregators, for which steep curves are common, suggest that these curves owe to stoichiometric inhibition, which predicts that IC₅₀ should vary linearly with enzyme concentration. Most steep dose-response curves in screening may be due to this effect.

View: Full Text HTML | Hi-Res PDF

Tools

SciFinder Links

History

Published In Issue December 14, 2006
Received September 21, 2006

Recommend & Share

Related Content

Effect of Detergent on “Promiscuous” InhibitorsJournal of Medicinal Chemistry
- Effect of Detergent on “Promiscuous” Inhibitors
  Ali J. Ryan, Norman M. Gray, Peter N. Lowe, and Chun-wa Chung
  Journal of Medicinal Chemistry 2003 46 (16), pp 3448–3451
  Abstract: The term “promiscuous” inhibitors has been coined for compounds whose inhibition mechanism involves the interaction of aggregates of many compound molecules with the target protein, rather than the binding of individual molecules. This paper demonstrates ...
  Abstract | Full Text HTML | Hi-Res PDF
A Specific Mechanism of Nonspecific InhibitionJournal of Medicinal Chemistry
- A Specific Mechanism of Nonspecific Inhibition
  Susan L. McGovern, Brian T. Helfand, Brian Feng, and Brian K. Shoichet
  Journal of Medicinal Chemistry 2003 46 (20), pp 4265–4272
  Abstract: Promiscuous small molecules plague screening libraries and hit lists. Previous work has found that several nonspecific compounds form submicrometer aggregates, and it has been suggested that this aggregate species is responsible for the inhibition of many ...
  Abstract | Full Text HTML | Hi-Res PDF
A Common Mechanism Underlying Promiscuous Inhibitors from Virtual and High-Throughput ScreeningJournal of Medicinal Chemistry
- A Common Mechanism Underlying Promiscuous Inhibitors from Virtual and High-Throughput Screening
  Susan L. McGovern, Emilia Caselli, Nikolaus Grigorieff, and Brian K. Shoichet
  Journal of Medicinal Chemistry 2002 45 (8), pp 1712–1722
  Abstract: High-throughput and virtual screening are widely used to discover novel leads for drug design. On examination, many screening hits appear non-drug-like: they act noncompetitively, show little relationship between structure and activity, and have poor ...
  Abstract | Full Text HTML | Hi-Res PDF

Letter

Interpreting Steep Dose-Response Curves in Early Inhibitor Discovery

Abstract

Tools

SciFinder Links

History

Recommend & Share

Related Content

Effect of Detergent on “Promiscuous” Inhibitors

A Specific Mechanism of Nonspecific Inhibition

A Common Mechanism Underlying Promiscuous Inhibitors from Virtual and High-Throughput Screening

Other ACS content by these authors:

JOURNALS

BOOKS

MAGAZINE

COMMUNITIES

DIRECTORIES & DATABASES