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Article

A Novel Approach for Characterizing Protein Ligand Complexes: Molecular Basis for Specificity of Small-Molecule Bcl-2 Inhibitors

Addition/Correction

Alexey A. Lugovskoy,^†^‡ Alexei I. Degterev,^§ Amr F. Fahmy,^‡ Pei Zhou,^‡ John D. Gross,^‡ Junying Yuan,^§ and Gerhard Wagner*^‡

Contribution from the Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, Massachusetts 02138, Department of Biochemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, and Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115

J. Am. Chem. Soc., 2002, 124 (7), pp 1234–1240

DOI: 10.1021/ja011239y

Publication Date (Web): January 25, 2002

†

Committee on Higher Degrees in Biophysics.

‡

Department of Biochemistry and Molecular Pharmacology.

Department of Cell Biology.

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

Phone: (617) 432−3213. Fax: (617) 432-4383. E-mail: gerhard_wagner@hms.harvard.edu.

Abstract

The increasing diversity of small molecule libraries has been an important source for the development of new drugs and, more recently, for unraveling the mechanisms of cellular eventsa process termed chemical genetics.¹ Unfortunately, the majority of currently available compounds are mechanism-based enzyme inhibitors, whereas most of cellular activity regulation proceeds on the level of protein−protein interactions. Hence, the development of small molecule inhibitors of protein−protein interactions is important. When screening compound libraries, low-micromolar inhibitors of protein interactions can be routinely found. The enhancement of affinities and rationalization of the binding mechanism require structural information about the protein−ligand complexes. Crystallization of low-affinity complexes is difficult, and their NMR analysis suffers from exchange broadening, which limits the number of obtainable intermolecular constraints. Here we present a novel method of ligand validation and optimization, which is based on the combination of structural and computational approaches. We successfully used this method to analyze the basis for structure−activity relationships of previously selected ² small molecule inhibitors of the antiapoptotic protein Bcl-xL and identified new members of this inhibitor family.