Pocket detection and interaction-weighted ligand-similarity search yields novel high-affinity binders for Myocilin-OLF, a protein implicated in glaucoma

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:27

Article

Srinivasan, Bharath¹  Tonddast-Navaei, Sam¹  Skolnick, Jeffrey¹ 

[1] Georgia Inst Technol, Sch Biol, Ctr Study Syst Biol, 950 Atlantic Dr, Atlanta, GA 30332 USA

关键词: Binding;    Myocilin;    Glaucoma;    Drug discovery;    Virtual ligand screening;    Thermal shift assay;   

DOI  :  10.1016/j.bmcl.2017.07.035

来源: Elsevier

【 摘 要 】

Traditional structure and ligand based virtual screening approaches rely on the availability of structural and ligand binding information. To overcome this limitation, hybrid approaches were developed that relied on extraction of ligand binding information from proteins sharing similar folds and hence, evolutionarily relationship. However, they cannot target a chosen pocket in a protein. To address this, a pocket centric virtual ligand screening approach is required. Here, we employ a new, iterative implementation of a pocket and ligand-similarity based approach to virtual ligand screening to predict small molecule binders for the olfactomedin domain of human myocilin implicated in glaucoma. Small-molecule binders of the protein might prevent the aggregation of the protein, commonly seen during glaucoma. First round experimental assessment of the predictions using differential scanning fluorimetry with myoc-OLF yielded 7 hits with a success rate of 12.7%; the best hit had an apparent dissociation constant of 99 nM. By matching to the key functional groups of the best ligand that were likely involved in binding, the affinity of the best hit was improved by almost 10,000 fold from the high nanomolar to the low picomolar range. Thus, this study provides preliminary validation of the methodology on a medically important glaucoma associated protein. (C) 2017 Elsevier Ltd. All rights reserved.

【 授权许可】

Free