Fragment Binding Can Be Either More Enthalpy-Driven or Entropy-Driven: Crystal Structures and Residual Hydration Patterns Suggest Why

In
lead optimization, small, enthalpically advantaged fragments
have been suggested to be superior, as an entropic component will
be added inevitably during late-stage optimization. Determination
of thermodynamic signatures of weak-binding fragments is essential
to support the decision-making process, to decide which fragment to
take to further optimization. High-resolution crystal structures of
six fragments binding to the S1 pocket of thrombin were determined
and analyzed with respect to their thermodynamic profile. The two
most potent fragments exhibiting an amidine-type scaffold are not
the most enthalpic binders; instead a chloro-thiophene fragment binds
more enthalpically. Two chemically very similar chloro-aromatic fragments
differ strongly in their potency (430 μM vs 10 mM); their binding
modes are related, but the surrounding residual water network differs.
The more potent one recruits a water molecule and involves Glu192
in binding, thus succeeding in firmly capping the S1 pocket. Fragments
exhibiting a rather perfect solvation pattern in their binding mode
also experience the highest potency.