Ye Che1, Garland R Marshall. 1. Washington University, Center for Computational Biology and Department of Biochemistry and Molecular Biophysics, St. Louis, MO 63110, USA.
Abstract
BACKGROUND: Protein-protein interactions dominate molecular recognition in biologic systems. One major challenge for drug discovery arises from the very large surfaces that are characteristic of many protein-protein interactions. OBJECTIVES: To identify 'drug-like' small molecule leads capable of modulating protein-protein interactions based on common protein-recognition motifs, such as alpha-helices, beta-strands, reverse-turns and polyproline motifs for example. OVERVIEW: Many proteins/peptides are unstructured under physiologic conditions and only fold into ordered structures on binding to their cellular targets. Therefore, preorganization of an inhibitor into its protein-bound conformation reduces the entropy of binding and enhances the relative affinity of the inhibitor. Accordingly, this review describes a general strategy to address the challenge based on the 'privileged structure hypothesis' [Che, PhD thesis, Washington University, 2003] that chemical templates capable of mimicking surfaces of protein-recognition motifs are potential privileged scaffolds as small-molecule inhibitors of protein-protein interactions. The authors highlight recent advances in the design of privileged scaffolds targeting reverse-turn and helical recognition. CONCLUSIONS: Privileged scaffolds targeting common protein-recognition motifs are useful to help elucidate the receptor-bound conformation and to provide non-peptidic, bioavailable substructures suitable for optimization to modulate protein-protein interactions.
BACKGROUND: Protein-protein interactions dominate molecular recognition in biologic systems. One major challenge for drug discovery arises from the very large surfaces that are characteristic of many protein-protein interactions. OBJECTIVES: To identify 'drug-like' small molecule leads capable of modulating protein-protein interactions based on common protein-recognition motifs, such as alpha-helices, beta-strands, reverse-turns and polyproline motifs for example. OVERVIEW: Many proteins/peptides are unstructured under physiologic conditions and only fold into ordered structures on binding to their cellular targets. Therefore, preorganization of an inhibitor into its protein-bound conformation reduces the entropy of binding and enhances the relative affinity of the inhibitor. Accordingly, this review describes a general strategy to address the challenge based on the 'privileged structure hypothesis' [Che, PhD thesis, Washington University, 2003] that chemical templates capable of mimicking surfaces of protein-recognition motifs are potential privileged scaffolds as small-molecule inhibitors of protein-protein interactions. The authors highlight recent advances in the design of privileged scaffolds targeting reverse-turn and helical recognition. CONCLUSIONS: Privileged scaffolds targeting common protein-recognition motifs are useful to help elucidate the receptor-bound conformation and to provide non-peptidic, bioavailable substructures suitable for optimization to modulate protein-protein interactions.
Authors: Xiachang Wang; Anna R Reynolds; Sherif I Elshahawi; Khaled A Shaaban; Larissa V Ponomareva; Meredith A Saunders; Ibrahim S Elgumati; Yinan Zhang; Gregory C Copley; James C Hower; Manjula Sunkara; Andrew J Morris; Madan K Kharel; Steven G Van Lanen; Mark A Prendergast; Jon S Thorson Journal: Org Lett Date: 2015-05-11 Impact factor: 6.005