edoc

Paying the Price of Desolvation in Solvent-Exposed Protein Pockets: Impact of Distal Solubilizing Groups on Affinity and Binding Thermodynamics in a Series of Thermolysin Inhibitors

Cramer, Jonathan and Krimmer, Stefan G. and Heine, Andreas and Klebe, Gerhard. (2017) Paying the Price of Desolvation in Solvent-Exposed Protein Pockets: Impact of Distal Solubilizing Groups on Affinity and Binding Thermodynamics in a Series of Thermolysin Inhibitors. Journal of Medicinal Chemistry, 60 (13). pp. 5791-5799.

Full text not available from this repository.

Official URL: https://edoc.unibas.ch/70159/

Downloads: Statistics Overview

Abstract

In lead optimization, open, solvent-exposed protein pockets are often disregarded as prospective binding sites. Because of bulk-solvent proximity, researchers are instead enticed to attach charged polar groups at inhibitor scaffolds to improve solubility and pharmacokinetic properties. It is rarely considered that solvent effects from water reorganization in the first hydration shell of protein-ligand complexes can have a significant impact on binding. We investigate the thermodynamic fingerprint of thermolysin inhibitors featuring terminal charged ammonium groups that are gradually pulled from a distal, solvent-exposed position into the flat, bowl-shaped S; 2; ' pocket. Even for the most remote attachment, costs for partial desolvation of the polar group next to the protein-solvent interface are difficult to compensate by interactions with the protein or surrounding water molecules. Through direct comparison with hydrophobic analogues, a significant 180-fold affinity loss was recorded, which questions popular strategies to attach polar ligand-solubilizing groups at the exposed terminus of substituents accommodated in flat open pockets.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molekulare Pharmazie (Ernst)
UniBasel Contributors:Cramer, Jonathan
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:1520-4804
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:16 Apr 2019 15:28
Deposited On:16 Apr 2019 15:28

Repository Staff Only: item control page