3 research outputs found
Robust Predictive Power of the Electrostatic Term at Shortened Intermolecular Distances
At distances shorter than equilibrium, electrostatic
interactions
seem to be a more robust indicator of relative molecular dimer stability
than more accurate electronic structure approaches. We arrive at this
conclusion by investigating the nonparametric correlation between
reference interaction energies at equilibrium geometries (coupled
cluster with singles, doubles, and perturbative triples at the complete
basis set limit, Δ<i>E</i><sub>CCSD(T)</sub><sup>CBS,ref</sup>) and its various approximate values
obtained at a range of distances for a training set of 22 biologically
relevant dimers. The reference and other costly methods start to fail
to reproduce the equilibrium ranking of dimer stabilities when the
intermolecular distance is shortened by more than 0.2 Å, but
the full electrostatic component (includes penetration) maintains
a high success rate. Such trends provide a new perspective for any
applications where inaccurate structures are used out of necessity,
such as the scoring of ligands docked to enzyme active sites
Robust Predictive Power of the Electrostatic Term at Shortened Intermolecular Distances
At distances shorter than equilibrium, electrostatic
interactions
seem to be a more robust indicator of relative molecular dimer stability
than more accurate electronic structure approaches. We arrive at this
conclusion by investigating the nonparametric correlation between
reference interaction energies at equilibrium geometries (coupled
cluster with singles, doubles, and perturbative triples at the complete
basis set limit, Δ<i>E</i><sub>CCSD(T)</sub><sup>CBS,ref</sup>) and its various approximate values
obtained at a range of distances for a training set of 22 biologically
relevant dimers. The reference and other costly methods start to fail
to reproduce the equilibrium ranking of dimer stabilities when the
intermolecular distance is shortened by more than 0.2 Å, but
the full electrostatic component (includes penetration) maintains
a high success rate. Such trends provide a new perspective for any
applications where inaccurate structures are used out of necessity,
such as the scoring of ligands docked to enzyme active sites
Physical Nature of Fatty Acid Amide Hydrolase Interactions with Its Inhibitors: Testing a Simple Nonempirical Scoring Model
Fatty
acid amide hydrolase (FAAH) is an enzyme responsible for
the deactivating hydrolysis of fatty acid ethanolamide neuromodulators.
FAAH inhibitors have gained considerable interest due to their possible
application in the treatment of anxiety, inflammation, and pain. In
the context of inhibitor design, the availability of reliable computational
tools for predicting binding affinity is still a challenging task,
and it is now well understood that empirical scoring functions have
several limitations that in principle could be overcome by quantum
mechanics. Herein, systematic ab initio analyses of FAAH interactions
with a series of inhibitors belonging to the class of the <i>N</i>-alkylcarbamic acid aryl esters have been performed. In
contrast to our earlier studies of other classes of enzyme–inhibitor
complexes, reasonable correlation with experimental results required
us to consider correlation effects along with electrostatic term.
Therefore, the simplest comprehensive nonempirical model allowing
for qualitative predictions of binding affinities for FAAH ligands
consists of electrostatic multipole and second-order dispersion terms.
Such a model has been validated against the relative stabilities of
the benchmark S66 set of biomolecular complexes. As it does not involve
parameters fitted to experimentally derived data, this model offers
a unique opportunity for generally applicable inhibitor design and
virtual screening