4 research outputs found
Predicting the Sites and Energies of Noncovalent Intermolecular Interactions Using Local Properties
Feed-forward artificial neural nets have been used to
recognize H-bond donor and acceptor sites on drug-like molecules based
on local properties (electron density, molecular electrostatic potential
and local ionization energy, electron affinity, and polarizability)
calculated at grid points around the molecule. Interaction energies
for training were obtained from B97-D and ωB97X-D/aug-cc-pVDZ
density-functional theory calculations on a series of model central
molecules and H-bond acceptor and donor probes constrained to the
grid points used for training. The resulting models provide maps of
both classical and unusual H- and halogen-bonding sites. Note that
these reactions result even though only classical H-bond donors and
acceptors were used as probes around the central molecules. Some examples
demonstrate the ability of the models to take the electronics of the
central molecule into consideration and to provide semiquantitative
estimates of interaction energies at low computational cost
Economical and Accurate Protocol for Calculating Hydrogen-Bond-Acceptor Strengths
A series
of density functional/basis set combinations and second-order
Møller–Plesset calculations have been used to test their
ability to reproduce the trends observed experimentally for the strengths
of hydrogen-bond acceptors in order to identify computationally efficient
techniques for routine use in the computational drug-design process.
The effects of functionals, basis sets, counterpoise corrections,
and constraints on the optimized geometries were tested and analyzed,
and recommendations (M06-2X/cc-pVDZ and X3LYP/cc-pVDZ with single-point
counterpoise corrections or X3LYP/aug-cc-pVDZ without counterpoise)
were made for suitable moderately high-throughput techniques
Quantum Mechanics-Based Properties for 3D-QSAR
We have used a set of four local
properties based on semiempirical
molecular orbital calculations (electron density (ρ), hydrogen
bond donor field (HDF), hydrogen bond acceptor field (HAF), and molecular
lipophilicity potential (MLP)) for 3D-QSAR studies to overcome the
limitations of the current force field-based molecular interaction
fields (MIFs). These properties can be calculated rapidly and are
thus amenable to high-throughput industrial applications. Their statistical
performance was compared with that of conventional 3D-QSAR approaches
using nine data sets (angiotensin converting enzyme inhibitors (ACE),
acetylcholinesterase inhibitors (AchE), benzodiazepine receptor ligands
(BZR), cyclooxygenase-2 inhibitors (COX2), dihydrofolate reductase
inhibitors (DHFR), glycogen phosphorylase b inhibitors (GPB), thermolysin
inhibitors (THER), thrombin inhibitors (THR), and serine protease
factor Xa inhibitors (fXa)). The 3D-QSAR models generated were tested
thoroughly for robustness and predictive ability. The average performance
of the quantum mechanical molecular interaction field (QM-MIF) models
for the nine data sets is better than that of the conventional force
field-based MIFs. In the individual data sets, the QM-MIF models always
perform better than, or as well as, the conventional approaches. It
is particularly encouraging that the relative performance of the QM-MIF
models improves in the external validation. In addition, the models
generated showed statistical stability with respect to model building
procedure variations such as grid spacing size and grid orientation.
QM-MIF contour maps reproduce the features important for ligand binding
for the example data set (factor Xa inhibitors), demonstrating the
intuitive chemical interpretability of QM-MIFs
Directional Noncovalent Interactions: Repulsion and Dispersion
The interaction energies between
an argon atom and the dihalogens
Br<sub>2</sub>, BrCl, and BrF have been investigated using frozen
core CCSD(T)(fc)/aug-cc-pVQZ calculations as reference values for
other levels of theory. The potential-energy hypersurfaces show two
types of minima: (1) collinear with the dihalogen bond and (2) in
a bridging position. The former represent the most stable minima for
these systems, and their binding energies decrease in the order Br
> Cl > F. Isotropic atom–atom potentials cannot reproduce
this
binding pattern. Of the other levels of theory, CCSD(T)(fc)/aug-cc-pVTZ
reproduces the reference data very well, as does MP2(fc)/aug-cc-pVDZ,
which performs better than MP2 with the larger basis sets (aug-cc-pVQZ
and aug-cc-pvTZ). B3LYP-D3 and M06-2X reproduce the binding patterns
moderately well despite the former using an isotropic dispersion potential
correction. B3LYP-D3(bj) performs even better. The success of the
B3LYP-D3 methods is because polar flattening of the halogens allows
the argon atom to approach more closely in the direction collinear
with the bond, so that the sum of dispersion potential and repulsion
is still negative at shorter distances than normally possible and
the minimum is deeper at the van der Waals distance. Core polarization
functions in the basis set and including the core orbitals in the
CCSD(T)(full) calculations lead to a uniform decrease of approximately
20% in the magnitudes of the calculated interaction energies. The
EXXRPA+@EXX (exact exchange random phase approximation) orbital-dependent
density functional also gives interaction energies that correlate
well with the highest level of theory but are approximately 10% low.
The newly developed EXXRPA+@dRPA functional represents a systematic
improvement on EXXRPA+@EXX