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Synthesis and Structure-Activity Relationships of Inhibitors That Target the C-Terminal MEEVD on Heat Shock Protein 90.

ABSTRACT: Herein, we describe the synthesis and structure-activity relationships of cyclic peptides designed to target heat shock protein 90 (Hsp90). Generating 19 compounds and evaluating their binding affinity reveals that increasing electrostatic interactions allows the compounds to bind more effectively with Hsp90 compared to the lead structure. Exchanging specific residues for lysine improves binding affinity for Hsp90, indicating some residues are not critical for interacting with the target, whereas others are essential. Replacing l- for d-amino acids produced compounds with decreased binding affinity compared to the parent structure, confirming the importance of conformation and identifying key residues most important for binding. Thus, a specific conformation and electrostatic interactions are required in order for these inhibitors to bind to Hsp90.

SUBMITTER: Rahimi MN

PROVIDER: S-EPMC6291811 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Synthesis and Structure-Activity Relationships of Inhibitors That Target the C-Terminal MEEVD on Heat Shock Protein 90.

Rahimi Marwa N MN Buckton Laura K LK Zaiter Samantha S SS Kho Jessica J Chan Vickie V Guo Aldwin A Konesan Jenane J Kwon SuHyeon S Lam Lok K O LKO Lawler Michael F MF Leong Michael M Moldovan Gabriel D GD Neale David A DA Thornton Gillian G McAlpine Shelli R SR

ACS medicinal chemistry letters 20171213 2

Herein, we describe the synthesis and structure-activity relationships of cyclic peptides designed to target heat shock protein 90 (Hsp90). Generating 19 compounds and evaluating their binding affinity reveals that increasing electrostatic interactions allows the compounds to bind more effectively with Hsp90 compared to the lead structure. Exchanging specific residues for lysine improves binding affinity for Hsp90, indicating some residues are not critical for interacting with the target, wherea ...[more]

PMID: 30555625

Dataset Information

Synthesis and Structure-Activity Relationships of Inhibitors That Target the C-Terminal MEEVD on Heat Shock Protein 90.

Publications

Synthesis and Structure-Activity Relationships of Inhibitors That Target the C-Terminal MEEVD on Heat Shock Protein 90.

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