5 research outputs found
Impact of Template Choice on Homology Model Efficiency in Virtual Screening
Homology
modeling is a reliable method of predicting the three-dimensional
structures of proteins that lack NMR or X-ray crystallographic data.
It employs the assumption that a structural resemblance exists between
closely related proteins. Despite the availability of many crystal
structures of possible templates, only the closest ones are chosen
for homology modeling purposes. To validate the aforementioned approach,
we performed homology modeling of four serotonin receptors (5-HT<sub>1A</sub>R, 5-HT<sub>2A</sub>R, 5-HT<sub>6</sub>R, 5-HT<sub>7</sub>R) for virtual screening purposes, using 10 available G-Protein Coupled
Receptors (GPCR) templates with diverse evolutionary distances to
the targets, with various approaches to alignment construction and
model building. The resulting models were further validated in two
steps by means of ligand docking and enrichment calculation, using
Glide software. The final quality of the models was determined in
virtual screening-like experiments by the AUROC score of the resulting
ROC curves. The outcome of this research showed that no correlation
between sequence identity and model quality was found, leading to
the conclusion that the closest phylogenetic relative is not always
the best template for homology modeling
Multi-Step Protocol for Automatic Evaluation of Docking Results Based on Machine Learning MethodsA Case Study of Serotonin Receptors 5‑HT<sub>6</sub> and 5‑HT<sub>7</sub>
Molecular
docking, despite its undeniable usefulness in computer-aided
drug design protocols and the increasing sophistication of tools used
in the prediction of ligand–protein interaction energies, is
still connected with a problem of effective results analysis. In this
study, a novel protocol for the automatic evaluation of numerous docking
results is presented, being a combination of Structural Interaction
Fingerprints and Spectrophores descriptors, machine-learning techniques,
and multi-step results analysis. Such an approach takes into consideration
the performance of a particular learning algorithm (five machine learning
methods were applied), the performance of the docking algorithm itself,
the variety of conformations returned from the docking experiment,
and the receptor structure (homology models were constructed on five
different templates). Evaluation using compounds active toward 5-HT<sub>6</sub> and 5-HT<sub>7</sub> receptors, as well as additional analysis
carried out for beta-2 adrenergic receptor ligands, proved that the
methodology is a viable tool for supporting virtual screening protocols,
enabling proper discrimination between active and inactive compounds
Multi-Step Protocol for Automatic Evaluation of Docking Results Based on Machine Learning MethodsA Case Study of Serotonin Receptors 5‑HT<sub>6</sub> and 5‑HT<sub>7</sub>
Molecular
docking, despite its undeniable usefulness in computer-aided
drug design protocols and the increasing sophistication of tools used
in the prediction of ligand–protein interaction energies, is
still connected with a problem of effective results analysis. In this
study, a novel protocol for the automatic evaluation of numerous docking
results is presented, being a combination of Structural Interaction
Fingerprints and Spectrophores descriptors, machine-learning techniques,
and multi-step results analysis. Such an approach takes into consideration
the performance of a particular learning algorithm (five machine learning
methods were applied), the performance of the docking algorithm itself,
the variety of conformations returned from the docking experiment,
and the receptor structure (homology models were constructed on five
different templates). Evaluation using compounds active toward 5-HT<sub>6</sub> and 5-HT<sub>7</sub> receptors, as well as additional analysis
carried out for beta-2 adrenergic receptor ligands, proved that the
methodology is a viable tool for supporting virtual screening protocols,
enabling proper discrimination between active and inactive compounds
Kinetic Models of Cyclosporin A in Polar and Apolar Environments Reveal Multiple Congruent Conformational States
The
membrane permeability of cyclic peptides and peptidomimetics,
which are generally larger and more complex than typical drug molecules,
is likely strongly influenced by the conformational behavior of these
compounds in polar and apolar environments. The size and complexity
of peptides often limit their bioavailability, but there are known
examples of peptide natural products such as cyclosporin A (CsA) that
can cross cell membranes by passive diffusion. CsA is an undecapeptide
with seven methylated backbone amides. Its crystal structure shows
a “closed” twisted β-pleated sheet conformation
with four intramolecular hydrogen bonds that is also observed in NMR
measurements of CsA in chloroform. When binding to its target cyclophilin,
on the other hand, CsA adopts an “open” conformation
without intramolecular hydrogen bonds. In this study, we attempted
to sample the complete conformational space of CsA in chloroform and
in water by molecular dynamics simulations in order to better understand
its conformational behavior in these two environments and to rationalize
the good membrane permeability of CsA observed experimentally. From
10 ÎĽs molecular dynamics simulations in each solvent, Markov
state models were constructed to characterize the metastable conformational
states. The model in chloroform is compared to nuclear Overhauser
effect NMR spectroscopy data reported in this study and taken from
the literature. The conformational landscapes in the two solvents
show significant overlap but also clearly distinct features
M-Chem: a modular software package for molecular simulation that spans scientific domains
We present a new software package called M-Chem that is designed from scratch in C++ and parallelised on shared-memory multi-core architectures to facilitate efficient molecular simulations. Currently, M-Chem is a fast molecular dynamics (MD) engine that supports the evaluation of energies and forces from two-body to many-body all-atom potentials, reactive force fields, coarse-grained models, combined quantum mechanics molecular mechanics (QM/MM) models, and external force drivers from machine learning, augmented by algorithms that are focused on gains in computational simulation times. M-Chem also includes a range of standard simulation capabilities including thermostats, barostats, multi-timestepping, and periodic cells, as well as newer methods such as fast extended Lagrangians and high quality electrostatic potential generation. At present M-Chem is a developer friendly environment in which we encourage new software contributors from diverse fields to build their algorithms, models, and methods in our modular framework. The long-term objective of M-Chem is to create an interdisciplinary platform for computational methods with applications ranging from biomolecular simulations, reactive chemistry, to materials research.</p