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The Role of Water Networks in Phosphodiesterase Inhibitor Dissociation and Kinetic Selectivity

Blaazer, Antoni R., Singh, Abhimanyu K., Zara, Lorena, Boronat, Pierre, Bautista, Lady J., Irving, Steve, Majewski, Maciej, Barril, Xavier, Wijtmans, Maikel, Danielson, U. Helena, and others. (2024) The Role of Water Networks in Phosphodiesterase Inhibitor Dissociation and Kinetic Selectivity. ChemMedChem, 19 (22). Article Number e202400417. ISSN 1860-7187. (doi:10.1002/cmdc.202400417) (KAR id:107290)

Abstract

AbstractIn search of new opportunities to develop Trypanosoma brucei phosphodiesterase B1 (TbrPDEB1) inhibitors that have selectivity over the off‐target human PDE4 (hPDE4), different stages of a fragment‐growing campaign were studied using a variety of biochemical, structural, thermodynamic, and kinetic binding assays. Remarkable differences in binding kinetics were identified and this kinetic selectivity was explored with computational methods, including molecular dynamics and interaction fingerprint analyses. These studies indicate that a key hydrogen bond between GlnQ.50 and the inhibitors is exposed to a water channel in TbrPDEB1, leading to fast unbinding. This water channel is not present in hPDE4, leading to inhibitors with a longer residence time. The computer‐aided drug design protocols were applied to a recently disclosed TbrPDEB1 inhibitor with a different scaffold and our results confirm that shielding this key hydrogen bond through disruption of the water channel represents a viable design strategy to develop more selective inhibitors of TbrPDEB1. Our work shows how computational protocols can be used to understand the contribution of solvent dynamics to inhibitor binding, and our results can be applied in the design of selective inhibitors for homologous PDEs found in related parasites.

Item Type: Article
DOI/Identification number: 10.1002/cmdc.202400417
Uncontrolled keywords: Inhibitors, Selectivity, Kinetics, Structure-based drug discovery, Computer-aided drug design
Subjects: Q Science
Q Science > QH Natural history
Divisions: Divisions > Division of Natural Sciences > Biosciences
Funders: Dutch Research Council (https://ror.org/04jsz6e67)
European Commission (https://ror.org/00k4n6c32)
SWORD Depositor: JISC Publications Router
Depositing User: JISC Publications Router
Date Deposited: 19 Nov 2024 15:00 UTC
Last Modified: 22 Nov 2024 14:35 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/107290 (The current URI for this page, for reference purposes)

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