5 research outputs found
xMaPAn Interpretable Alignment-Free Four-Dimensional Quantitative Structure–Activity Relationship Technique Based on Molecular Surface Properties and Conformer Ensembles
A novel alignment-free molecular
descriptor called xMaP (flexible
MaP descriptor) is introduced. The descriptor is the advancement of
the previously published translationally and rotationally invariant
three-dimensional (3D) descriptor MaP (mapping property distributions
onto the molecular surface) to the fourth dimension (4D). In addition
to MaP, xMaP is independent of the chosen starting conformation of
the encoded molecules and is therefore entirely alignment-free. This
is achieved by using ensembles of conformers, which are generated
by conformational searches. This step of the procedure is similar
to Hopfinger’s 4D quantitative structure–activity relationship
(QSAR). A five-step procedure is used to compute the xMaP descriptor.
First, a conformational search for each molecule is carried out. Next,
for each of the conformers an approximation to the molecular surface
with equally distributed surface points is computed. Third, molecular
properties are projected onto this surface. Fourth, areas of identical
properties are clustered to so-called patches. Fifth, the spatial
distribution of the patches is converted into an alignment-free descriptor
that is based on the entire conformer ensemble. The resulting descriptor
can be interpreted by superimposing the most important descriptor
variables and the molecules of the data set. The most important descriptor
variables are identified with chemometric regression tools. The novel
descriptor was applied to several benchmark data sets and was compared
to other descriptors and QSAR techniques comprising a binary fingerprint,
a topological pharmacophore descriptor (Cats2D), and the field-based
3D-QSAR technique GRID/PLS which is alignment-dependent. The use of
conformer ensembles renders xMaP very robust. It turns out that xMaP
performs very well on (almost) all data sets and that the statistical
results are comparable to GRID/PLS. In addition to that, xMaP can
also be used to efficiently visualize the derived quantitative structure–activity
relationships
MOESM4 of Efficiency of different measures for defining the applicability domain of classification models
Additional file 4. Source of the data
Operator theory and its applications: in memory of V. B. Lidskii (1924-2008)
This book is a collection of articles devoted to the theory of linear operators in Hilbert spaces and its applications. The subjects covered range from the abstract theory of Toeplitz operators to the analysis of very specific differential operators arising in quantum mechanics, electromagnetism, and the theory of elasticity; the stability of numerical methods is also discussed. Many of the articles deal with spectral problems for not necessarily selfadjoint operators. Some of the articles are surveys outlining the current state of the subject and presenting open problems
A Diverse Benchmark Based on 3D Matched Molecular Pairs for Validating Scoring Functions
The
prediction of protein–ligand interactions and their
corresponding binding free energy is a challenging task in structure-based
drug design and related applications. Docking and scoring is broadly
used to propose the binding mode and underlying interactions as well
as to provide a measure for ligand affinity or differentiate between
active and inactive ligands. Various studies have revealed that most
docking software packages reliably predict the binding mode, although
scoring remains a challenge. Here, a diverse benchmark data set of
99 matched molecular pairs (3D-MMPs) with experimentally determined
X-ray structures and corresponding binding affinities is introduced.
This data set was used to study the predictive power of 13 commonly
used scoring functions to demonstrate the applicability of the 3D-MMP
data set as a valuable tool for benchmarking scoring functions
10-Iodo-11<i>H</i>‑indolo[3,2‑<i>c</i>]quinoline-6-carboxylic Acids Are Selective Inhibitors of DYRK1A
The protein kinase DYRK1A has been
suggested to act as one of the
intracellular regulators contributing to neurological alterations
found in individuals with Down syndrome. For an assessment of the
role of DYRK1A, selective synthetic inhibitors are valuable pharmacological
tools. However, the DYRK1A inhibitors described in the literature
so far either are not sufficiently selective or have not been tested
against closely related kinases from the DYRK and the CLK protein
kinase families. The aim of this study was the identification of DYRK1A
inhibitors exhibiting selectivity versus the structurally and functionally
closely related DYRK and CLK isoforms. Structure modification of the
screening hit 11<i>H</i>-indoloÂ[3,2-<i>c</i>]Âquinoline-6-carboxylic
acid revealed structure–activity relationships for kinase inhibition
and enabled the design of 10-iodo-substituted derivatives as very
potent DYRK1A inhibitors with considerable selectivity against CLKs.
X-ray structure determination of three 11<i>H</i>-indoloÂ[3,2-<i>c</i>]Âquinoline-6-carboxylic acids cocrystallized with DYRK1A
confirmed the predicted binding mode within the ATP binding site