TY - JOUR
T1 - Privileged scaffolds targeting reverse-turn and helix recognition
AU - Che, Ye
AU - Marshall, Garland R.
PY - 2008/1
Y1 - 2008/1
N2 - 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 α-helices, β-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.
AB - 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 α-helices, β-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.
KW - Drug discovery
KW - Helix
KW - Interaction
KW - Privileged structure
KW - Protein-protein reverse turn
UR - http://www.scopus.com/inward/record.url?scp=39049124587&partnerID=8YFLogxK
U2 - 10.1517/14728222.12.1.101
DO - 10.1517/14728222.12.1.101
M3 - Review article
C2 - 18076374
AN - SCOPUS:39049124587
VL - 12
SP - 101
EP - 114
JO - Expert Opinion on Therapeutic Targets
JF - Expert Opinion on Therapeutic Targets
SN - 1472-8222
IS - 1
ER -