5 research outputs found
Quantum Mechanics-Based Properties for 3D-QSAR
We have used a set of four local
properties based on semiempirical
molecular orbital calculations (electron density (Ï), 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
Thermodynamic Characterization of Hydration Sites from Integral Equation-Derived Free Energy Densities: Application to Protein Binding Sites and Ligand Series
Water
molecules play an essential role for mediating interactions
between ligands and protein binding sites. Displacement of specific
water molecules can favorably modulate the free energy of binding
of proteinâligand complexes. Here, the nature of water interactions
in protein binding sites is investigated by 3D RISM (three-dimensional
reference interaction site model) integral equation theory to understand
and exploit local thermodynamic features of water molecules by ranking
their possible displacement in structure-based design. Unlike molecular
dynamics-based approaches, 3D RISM theory allows for fast and noise-free
calculations using the same detailed level of soluteâsolvent
interaction description. Here we correlate molecular water entities
instead of mere site density maxima with local contributions to the
solvation free energy using novel algorithms. Distinct water molecules
and hydration sites are investigated in multiple proteinâligand
X-ray structures, namely streptavidin, factor Xa, and factor VIIa,
based on 3D RISM-derived free energy density fields. Our approach
allows the semiquantitative assessment of whether a given structural
water molecule can potentially be targeted for replacement in structure-based
design. Finally, PLS-based regression models from free energy density
fields used within a 3D-QSAR approach (CARMa - comparative analysis
of 3D RISM Maps) are shown to be able to extract relevant information
for the interpretation of structureâactivity relationship (SAR)
trends, as demonstrated for a series of serine protease inhibitors
Discovery and Optimization of 1âPhenoxy-2-aminoindanes as Potent, Selective, and Orally Bioavailable Inhibitors of the Na<sup>+</sup>/H<sup>+</sup> Exchanger Type 3 (NHE3)
The design, synthesis, and structureâactivity
relationship
of 1-phenoxy-2-aminoindanes as inhibitors of the Na<sup>+</sup>/H<sup>+</sup> exchanger type 3 (NHE3) are described based on a hit from
high-throughput screening (HTS). The chemical optimization resulted
in the discovery of potent, selective, and orally bioavailable NHE3
inhibitors with <b>13d</b> as best compound, showing high in
vitro permeability and lacking CYP2D6 inhibition
as main optimization parameters. Aligning 1-phenoxy-2-aminoindanes
onto the X-ray structure of <b>13d</b> then provided 3D-QSAR
models for NHE3 inhibition capturing guidelines for optimization.
These models showed good correlation coefficients and allowed for
activity estimation. In silico ADMET models for Caco-2 permeability
and CYP2D6 inhibition were also successfully applied for this series.
Moreover, docking into the CYP2D6 X-ray structure provided a reliable
alignment for 3D-QSAR models. Finally <b>13d</b>, renamed as
SAR197, was characterized in vitro and by in vivo pharmacokinetic
(PK) and pharmacological studies to unveil its potential for reduction
of obstructive sleep apneas
Discovery and Optimization of 1âPhenoxy-2-aminoindanes as Potent, Selective, and Orally Bioavailable Inhibitors of the Na<sup>+</sup>/H<sup>+</sup> Exchanger Type 3 (NHE3)
The design, synthesis, and structureâactivity
relationship
of 1-phenoxy-2-aminoindanes as inhibitors of the Na<sup>+</sup>/H<sup>+</sup> exchanger type 3 (NHE3) are described based on a hit from
high-throughput screening (HTS). The chemical optimization resulted
in the discovery of potent, selective, and orally bioavailable NHE3
inhibitors with <b>13d</b> as best compound, showing high in
vitro permeability and lacking CYP2D6 inhibition
as main optimization parameters. Aligning 1-phenoxy-2-aminoindanes
onto the X-ray structure of <b>13d</b> then provided 3D-QSAR
models for NHE3 inhibition capturing guidelines for optimization.
These models showed good correlation coefficients and allowed for
activity estimation. In silico ADMET models for Caco-2 permeability
and CYP2D6 inhibition were also successfully applied for this series.
Moreover, docking into the CYP2D6 X-ray structure provided a reliable
alignment for 3D-QSAR models. Finally <b>13d</b>, renamed as
SAR197, was characterized in vitro and by in vivo pharmacokinetic
(PK) and pharmacological studies to unveil its potential for reduction
of obstructive sleep apneas
Probing Factor Xa ProteinâLigand Interactions: Accurate Free Energy Calculations and Experimental Validations of Two Series of High-Affinity Ligands
The accurate prediction of proteinâligand binding
affinity
belongs to one of the central goals in computer-based drug design.
Molecular dynamics (MD)-based free energy calculations have become
increasingly popular in this respect due to their accuracy and solid
theoretical basis. Here, we present a combined study which encompasses
experimental and computational studies on two series of factor Xa
ligands, which enclose a broad chemical space including large modifications
of the central scaffold. Using this integrated approach, we identified
several new ligands with different heterocyclic scaffolds different
from the previously identified indole-2-carboxamides that show superior
or similar affinity. Furthermore, the so far underexplored terminal
alkyne moiety proved to be a suitable non-classical bioisosteric replacement
for the higher halogenâÏ aryl interactions. With this
challenging example, we demonstrated the ability of the MD-based non-equilibrium
free energy calculation approach for guiding crucial modifications
in the lead optimization process, such as scaffold replacement and
single-site modifications at molecular interaction hot spots