14 research outputs found
Novel pharmacological maps of protein lysine methyltransferases: key for target deorphanization
Epigenetic therapies are being investigated for the treatment of cancer, cognitive disorders, metabolic alterations and
autoinmune diseases. Among the diferent epigenetic target families, protein lysine methyltransferases (PKMTs), are
especially interesting because it is believed that their inhibition may be highly specifc at the functional level. Despite
its relevance, there are currently known inhibitors against only 10 out of the 50 SET-domain containing members of
the PKMT family. Accordingly, the identifcation of chemical probes for the validation of the therapeutic impact of
epigenetic modulation is key. Moreover, little is known about the mechanisms that dictate their substrate specifcity and ligand selectivity. Consequently, it is desirable to explore novel methods to characterize the pharmacological similarity of PKMTs, going beyond classical phylogenetic relationships. Such characterization would enable the
prediction of ligand of-target efects caused by lack of ligand selectivity and the repurposing of known compounds
against alternative targets. This is particularly relevant in the case of orphan targets with unreported inhibitors. Here,
we frst perform a systematic study of binding modes of cofactor and substrate bound ligands with all available SET
domain-containing PKMTs. Protein ligand interaction fngerprints were applied to identify conserved hot spots and
contact-specifc residues across subfamilies at each binding site; a relevant analysis for guiding the design of novel,
selective compounds. Then, a recently described methodology (GPCR-CoINPocket) that incorporates ligand contact
information into classical alignment-based comparisons was applied to the entire family of 50 SET-containing proteins
to devise pharmacological similarities between them. The main advantage of this approach is that it is not restricted
to proteins for which crystallographic data with bound ligands is available. The resulting family organization from the
separate analysis of both sites (cofactor and substrate) was retrospectively and prospectively validated. Of note, three
hits (inhibition>50% at 10 µM) were identifed for the orphan NSD1
Towards the understanding of the activity of G9a inhibitors: an activity landscape and molecular modeling approach
In this work, we analyze the structure–activity relationships (SAR) of epigenetic inhibitors (lysine mimetics) against lysine
methyltransferase (G9a or EHMT2) using a combined activity landscape, molecular docking and molecular dynamics
approach. The study was based on a set of 251 G9a inhibitors with reported experimental activity. The activity landscape
analysis rapidly led to the identifcation of activity clifs, scafolds hops and other active an inactive molecules with distinct
SAR. Structure-based analysis of activity clifs, scafold hops and other selected active and inactive G9a inhibitors by means
of docking followed by molecular dynamics simulations led to the identifcation of interactions with key residues involved
in activity against G9a, for instance with ASP 1083, LEU 1086, ASP 1088, TYR 1154 and PHE 1158. The outcome of this
work is expected to further advance the development of G9a inhibitors
CHEMDNER: The drugs and chemical names extraction challenge
Natural language processing (NLP) and text mining technologies for the chemical domain (ChemNLP or chemical
text mining) are key to improve the access and integration of information from unstructured data such as patents
or the scientific literature. Therefore, the BioCreative organizers posed the CHEMDNER (chemical compound and
drug name recognition) community challenge, which promoted the development of novel, competitive and
accessible chemical text mining systems. This task allowed a comparative assessment of the performance of various
methodologies using a carefully prepared collection of manually labeled text prepared by specially trained
chemists as Gold Standard data. We evaluated two important aspects: one covered the indexing of documents
with chemicals (chemical document indexing - CDI task), and the other was concerned with finding the exact
mentions of chemicals in text (chemical entity mention recognition - CEM task). 27 teams (23 academic and
4 commercial, a total of 87 researchers) returned results for the CHEMDNER tasks: 26 teams for CEM and 23 for the
CDI task. Top scoring teams obtained an F-score of 87.39% for the CEM task and 88.20% for the CDI task, a very
promising result when compared to the agreement between human annotators (91%). The strategies used to
detect chemicals included machine learning methods (e.g. conditional random fields) using a variety of features,
chemistry and drug lexica, and domain-specific rules. We expect that the tools and resources resulting from this
effort will have an impact in future developments of chemical text mining applications and will form the basis to
find related chemical information for the detected entities, such as toxicological or pharmacogenomic properties
Immunomodulatory properties of carvone inhalation and Its effects on contextual fear memory in mice
A complex network of interactions exists between the immune, the olfactory, and the central nervous system (CNS). Inhalation of different fragrances can affect immunological reactions in response to an antigen but also may have effects on the CNS and cognitive activity. We performed an exploratory study of the immunomodulatory ability of a series of compounds representing each of the 10 odor categories or clusters described previously. We evaluated the impact of each particular odor on the immune response after immunization with the model antigen ovalbumin in combination with the TLR3 agonist poly I:C. We found that some odors behave as immunostimulatory agents, whereas others might be considered as potential immunosuppressant odors. Interestingly, the immunomodulatory capacity was, in some cases, strain-specific. In particular, one of the fragrances, carvone, was found to be immunostimulatory in BALB/c mice and immunosuppressive in C57BL/6J mice, facilitating or impairing viral clearance, respectively, in a model of a viral infection with a recombinant adenovirus. Importantly, inhalation of the odor improved the memory capacity in BALB/c mice in a fear-conditioning test, while it impaired this same capacity in C57BL/6J mice. The improvement in memory capacity in BALB/c was associated with higher CD3+ T cell infiltration into the hippocampus and increased local expression of mRNA coding for IL-1β, TNF-α, and IL-6 cytokines. In contrast, the memory impairment in C57BL/6 was associated with a reduction in CD3 numbers and an increase in IFN-γ. These data suggest an association between the immunomodulatory capacity of smells and their impact on the cognitive functions of the animals. These results highlight the potential of studying odors as therapeutic agents for CNS-related diseases
The CHEMDNER corpus of chemicals and drugs and its annotation principles
The automatic extraction of chemical information from text requires the recognition of chemical entity mentions as one
of its key steps. When developing supervised named entity recognition (NER) systems, the availability of a large,
manually annotated text corpus is desirable. Furthermore, large corpora permit the robust evaluation and comparison
of different approaches that detect chemicals in documents. We present the CHEMDNER corpus, a collection of 10,000
PubMed abstracts that contain a total of 84,355 chemical entity mentions labeled manually by expert chemistry
literature curators, following annotation guidelines specifically defined for this task. The abstracts of the CHEMDNER
corpus were selected to be representative for all major chemical disciplines. Each of the chemical entity mentions was
manually labeled according to its structure-associated chemical entity mention (SACEM) class: abbreviation, family,
formula, identifier, multiple, systematic and trivial. The difficulty and consistency of tagging chemicals in text was
measured using an agreement study between annotators, obtaining a percentage agreement of 91. For a subset of the
CHEMDNER corpus (the test set of 3,000 abstracts) we provide not only the Gold Standard manual annotations, but also
mentions automatically detected by the 26 teams that participated in the BioCreative IV CHEMDNER chemical mention
recognition task. In addition, we release the CHEMDNER silver standard corpus of automatically extracted mentions
from 17,000 randomly selected PubMed abstracts. A version of the CHEMDNER corpus in the BioC format has been
generated as well. We propose a standard for required minimum information about entity annotations for the
construction of domain specific corpora on chemical and drug entities. The CHEMDNER corpus and annotation
guidelines are available at: http://www.biocreative.org/resources/biocreative-iv/chemdner-corpus
Novel pharmacological maps of protein lysine methyltransferases: key for target deorphanization
Epigenetic therapies are being investigated for the treatment of cancer, cognitive disorders, metabolic alterations and
autoinmune diseases. Among the diferent epigenetic target families, protein lysine methyltransferases (PKMTs), are
especially interesting because it is believed that their inhibition may be highly specifc at the functional level. Despite
its relevance, there are currently known inhibitors against only 10 out of the 50 SET-domain containing members of
the PKMT family. Accordingly, the identifcation of chemical probes for the validation of the therapeutic impact of
epigenetic modulation is key. Moreover, little is known about the mechanisms that dictate their substrate specifcity and ligand selectivity. Consequently, it is desirable to explore novel methods to characterize the pharmacological similarity of PKMTs, going beyond classical phylogenetic relationships. Such characterization would enable the
prediction of ligand of-target efects caused by lack of ligand selectivity and the repurposing of known compounds
against alternative targets. This is particularly relevant in the case of orphan targets with unreported inhibitors. Here,
we frst perform a systematic study of binding modes of cofactor and substrate bound ligands with all available SET
domain-containing PKMTs. Protein ligand interaction fngerprints were applied to identify conserved hot spots and
contact-specifc residues across subfamilies at each binding site; a relevant analysis for guiding the design of novel,
selective compounds. Then, a recently described methodology (GPCR-CoINPocket) that incorporates ligand contact
information into classical alignment-based comparisons was applied to the entire family of 50 SET-containing proteins
to devise pharmacological similarities between them. The main advantage of this approach is that it is not restricted
to proteins for which crystallographic data with bound ligands is available. The resulting family organization from the
separate analysis of both sites (cofactor and substrate) was retrospectively and prospectively validated. Of note, three
hits (inhibition>50% at 10 µM) were identifed for the orphan NSD1
Towards the understanding of the activity of G9a inhibitors: an activity landscape and molecular modeling approach
In this work, we analyze the structure–activity relationships (SAR) of epigenetic inhibitors (lysine mimetics) against lysine
methyltransferase (G9a or EHMT2) using a combined activity landscape, molecular docking and molecular dynamics
approach. The study was based on a set of 251 G9a inhibitors with reported experimental activity. The activity landscape
analysis rapidly led to the identifcation of activity clifs, scafolds hops and other active an inactive molecules with distinct
SAR. Structure-based analysis of activity clifs, scafold hops and other selected active and inactive G9a inhibitors by means
of docking followed by molecular dynamics simulations led to the identifcation of interactions with key residues involved
in activity against G9a, for instance with ASP 1083, LEU 1086, ASP 1088, TYR 1154 and PHE 1158. The outcome of this
work is expected to further advance the development of G9a inhibitors
Taking advantage of the selectivity of histone deacetylases and phosphodiesterase inhibitors to design better therapeutic strategies to treat alzheimer’s disease
The discouraging results with therapies for Alzheimer’s disease (AD) in clinical trials,
highlights the urgent need to adopt new approaches. Like other complex diseases,
it is becoming clear that AD therapies should focus on the simultaneous modulation
of several targets implicated in the disease. Recently, using reference compounds
and the first-in class CM-414, we demonstrated that the simultaneous inhibition
of histone deacetylases [class I histone deacetylases (HDACs) and HDAC6] and
phosphodiesterase 5 (PDE5) has a synergistic therapeutic effect in AD models. To identify
the best inhibitory balance of HDAC isoforms and PDEs that provides a safe and efficient
therapy to combat AD, we tested the compound CM-695 in the Tg2576 mouse model
of this disease. CM-695 selectively inhibits HDAC6 over class I HDAC isoforms, which
largely overcomes the toxicity associated with HDAC class 1 inhibition. Furthermore,
CM-695 inhibits PDE9, which is expressed strongly in the brain and has been proposed
as a therapeutic target for AD. Chronic treatment of aged Tg2576 mice with CM-695
ameliorates memory impairment and diminishes brain Aβ, although its therapeutic effect
was no longer apparent 4 weeks after the treatment was interrupted. An increase in
the presence of 78-KDa glucose regulated protein (GRP78) and heat shock protein 70
(Hsp70) chaperones may underlie the therapeutic effect of CM-695. In summary, chronic
treatment with CM-695 appears to reverse the AD phenotype in a safe and effective
manner. Taking into account that AD is a multifactorial disorder, the multimodal action
of these compounds and the different events they affect may open new avenues to
combat AD
Taking advantage of the selectivity of histone deacetylases and phosphodiesterase inhibitors to design better therapeutic strategies to treat alzheimer’s disease
The discouraging results with therapies for Alzheimer’s disease (AD) in clinical trials,
highlights the urgent need to adopt new approaches. Like other complex diseases,
it is becoming clear that AD therapies should focus on the simultaneous modulation
of several targets implicated in the disease. Recently, using reference compounds
and the first-in class CM-414, we demonstrated that the simultaneous inhibition
of histone deacetylases [class I histone deacetylases (HDACs) and HDAC6] and
phosphodiesterase 5 (PDE5) has a synergistic therapeutic effect in AD models. To identify
the best inhibitory balance of HDAC isoforms and PDEs that provides a safe and efficient
therapy to combat AD, we tested the compound CM-695 in the Tg2576 mouse model
of this disease. CM-695 selectively inhibits HDAC6 over class I HDAC isoforms, which
largely overcomes the toxicity associated with HDAC class 1 inhibition. Furthermore,
CM-695 inhibits PDE9, which is expressed strongly in the brain and has been proposed
as a therapeutic target for AD. Chronic treatment of aged Tg2576 mice with CM-695
ameliorates memory impairment and diminishes brain Aβ, although its therapeutic effect
was no longer apparent 4 weeks after the treatment was interrupted. An increase in
the presence of 78-KDa glucose regulated protein (GRP78) and heat shock protein 70
(Hsp70) chaperones may underlie the therapeutic effect of CM-695. In summary, chronic
treatment with CM-695 appears to reverse the AD phenotype in a safe and effective
manner. Taking into account that AD is a multifactorial disorder, the multimodal action
of these compounds and the different events they affect may open new avenues to
combat AD