Jump to main content
Jump to site search


Effective lead optimization targeting the displacement of bridging receptor–ligand water molecules

Author affiliations

Abstract

Enhancing the binding affinities of ligands by means of lead modifications that displace bridging water molecules at protein–ligand interfaces is an important and widely studied lead optimization strategy. However, it is still challenging to ensure the success of this lead optimization strategy. Here we use theoretical derivations, which are then validated using reported experimental data, to identify the major determining factors in lead optimization designed to displace bridging water molecules. Our findings demonstrate that the nature of hydrogen-bond pairing between the ligand and protein polar atom(s) is the principal factor displacing interface water molecules, and not the binding strength of the water molecule. Our results also indicate that all interfacing bridging water molecules can potentially be targeted for displacement using this new approach. In summary, we show that strong–strong/weak–weak hydrogen-bond pairings of ligand atoms with protein atoms may provide useful guidance in lead modifications by designing modified ligands with higher binding affinities than their lead molecules. This study can help to increase the efficiency of rational drug design.

Graphical abstract: Effective lead optimization targeting the displacement of bridging receptor–ligand water molecules

Back to tab navigation

Supplementary files

Publication details

The article was received on 29 Jun 2018, accepted on 30 Aug 2018 and first published on 31 Aug 2018


Article type: Paper
DOI: 10.1039/C8CP04118K
Citation: Phys. Chem. Chem. Phys., 2018, Advance Article
  •   Request permissions

    Effective lead optimization targeting the displacement of bridging receptor–ligand water molecules

    D. Chen, Y. Li, M. Zhao, W. Tan, X. Li, T. Savidge, W. Guo and X. Fan, Phys. Chem. Chem. Phys., 2018, Advance Article , DOI: 10.1039/C8CP04118K

Search articles by author

Spotlight

Advertisements