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Ligand binding cooperativity: Bioisosteric replacement of CO with SO2 among thrombin inhibitors.

Abstract：

:Ligand-protein binding is a complex process that involves the formation of number of non-covalent interactions, e.g. H-bonds and hydrophobic interactions, between the ligand and the protein host. Upon binding, ligand functional groups can act synergistically (positive cooperativity) to improve the overall ligand binding affinity beyond what would be expected from their individual contributions. In this study, using thrombin as a protein model system, we evaluated the effect of the bioisosteric replacement of a carbonyl functionality with a sulphonyl functionality on positive cooperativity between their H-bonds with thrombin and hydrophobic binding in the adjacent S3 pocket. The positive cooperativity observed was greatly reduced when replacing the carbonyl group with a sulphonyl group. Evaluating how bioisosteric replacements affect cooperativity is important for making better informed ligand optimization SAR decisions.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Said AM,Hangauer DG

doi

10.1016/j.bmcl.2016.07.024

subject

Has Abstract

pub_date

2016-08-15 00:00:00

pages

3850-4

issue

16

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(16)30737-5

journal_volume

26

pub_type

杂志文章

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