Obdulia Rabal

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/

Chemical Interrogation of FOXO3a Nuclear Translocation Identifies Potent and Selective Inhibitors of Phosphoinositide 3-Kinases

Activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is one the most frequent genetic events in human cancer. A cell-based imaging assay that monitored the translocation of the Akt effector protein, Forkhead box O (FOXO), from the cytoplasm to the nucleus was employed to screen a collection of 33,992 small molecules. The positive compounds were used to screen kinases known to be involved in FOXO translocation. Pyrazolopyrimidine derivatives were found to be potent FOXO relocators as well as biochemical inhibitors of PI3Kα. A combination of virtual screening and molecular modeling led to the development of a structure-activity relationship, which indicated the preferred substituents on the pyrazolopyrimidine scaffold. This leads to the synthesis of ETP-45658, which is a potent and selective inhibitor of phosphoinositide 3-kinases and demonstrates mechanism of action in tumor cell lines and in vivo in treated mice.

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.

Comparison of Ligand-Based and Receptor-Based Virtual Screening of HIV Entry Inhibitors for the CXCR4 and CCR5 Receptors Using 3D Ligand Shape Matching and Ligand−Receptor Docking

HIV infection is initiated by fusion of the virus with the target cell through binding of the viral gp120 protein with the CD4 cell surface receptor protein and the CXCR4 or CCR5 co-receptors. There is currently considerable interest in developing novel ligands that can modulate the conformations of these co-receptors and, hence, ultimately block virus-cell fusion. This article describes a detailed comparison of the performance of receptor-based and ligand-based virtual screening approaches to find CXCR4 and CCR5 antagonists that could potentially serve as HIV entry inhibitors. Because no crystal structures for these proteins are available, homology models of CXCR4 and CCR5 have been built, using bovine rhodopsin as the template. For ligand-based virtual screening, several shape-based and property-based molecular comparison approaches have been compared, using high-affinity ligands as query molecules. These methods were compared by virtually screening a library assembled by us, consisting of 602 known CXCR4 and CCR5 inhibitors and some 4700 similar presumed inactive molecules. For each receptor, the library was queried using known binders, and the enrichment factors and diversity of the resulting virtual hit lists were analyzed. Overall, ligand-based shape-matching searches yielded higher enrichments than receptor-based docking, especially for CXCR4. The results obtained for CCR5 suggest the possibility that different active scaffolds bind in different ways within the CCR5 pocket.

APIF: A New Interaction Fingerprint Based on Atom Pairs and Its Application to Virtual Screening

A new interaction fingerprint (IF) called APIF (atom-pairs-based interaction fingerprint) has been developed for postprocessing protein-ligand docking results. Unlike other existing fingerprints which employ absolute locations of individual interactions, APIF considers the relative positions of pairs of interacting atoms. Docking-based virtual screening was performed with GOLD using the crystal structures of trypsin, rhinovirus, HIV protease, carboxypeptidase, and estrogen receptor-alpha as targets. A score derived from the similarity of the bit strings for each docking solution to that of a known reference binding mode was obtained. Comparisons between APIF, GoldScore function, and standard interaction fingerprint (CHIF) scores were performed using enrichment plots. Superior recovery rates were observed in the IF score cases. Comparable results were achieved by using either of the two interaction fingerprints, substantially improving GoldScore function enrichment factors. Binding mode analyses were also carried out in order to study the best method for selecting conformations with a binding mode similar to that of the reference crystallized complex. These showed that the first conformations retrieved by interaction fingerprint scores had a more similar binding mode to the reference complex than those retrieved by the GoldScore function.

Discovery of Mitogen-Activated Protein Kinase-Interacting Kinase 1 Inhibitors by a Comprehensive Fragment-Oriented Virtual Screening Approach

Mitogen-activated protein kinase-interacting kinases 1 and 2 (MNK1 and MNK2) phosphorylate the oncogene eIF4E on serine 209. This phosphorylation has been reported to be required for its oncogenic activity. To investigate if pharmacological inhibition of MNK1 could be useful for the treatment of cancers, we pursued a comprehensive virtual screening approach to rapidly identify pharmacological tools for target validation and to find optimal starting points for a plausible medicinal chemistry project. A collection of 1236 compounds, selected from a library of 42 168 compounds and a database of 18.8 million structures, were assayed. Of the identified hits, 26 were found to have IC(50) values less than 10 μM (2.10% hit rate). The most potent compound had an IC(50) value of 117 nM, and 73.1% of these hits were fragments. The hits were characterized by a high ligand efficiency (0.32-0.52 kcal/mol per heavy atom). Ten different chemical scaffolds were represented, giving a chemotype/hit ratio of 0.38.

Imidazo[1,2-a]pyrazines as novel PI3K inhibitors.

Phosphoinositide-3-kinase (PI3K) is an important target for cancer therapeutics due to the deregulation of its signaling pathway in a wide variety of human cancers. We describe herein a novel series of imidazo[1,2-a]pyrazines as PI3K inhibitors.

Conformational Selection versus Induced Fit in Kinases: The Case of PI3K‐γ

Molecular recognition is crucial for a multitude of fundamental biological processes, for example enzyme activation and inhibition, 2] and protein folding. The increasing availability of high-resolution structures of ligands bound to receptors has changed our understanding of molecular recognition from a static concept, in which interactions are considered to be a rigid lock and key, to a dynamic one, in which both the ligand and its target can assume different, yet not always complementary, shapes. Within this dynamic framework, two limiting mechanisms have been proposed: conformational selection 6] and induced fit. The first theory implies that there is a significant overlap between the conformational space that is occupied by the bound and unbound forms of the target, and that the role of the ligand is to stabilize certain conformations that are accessible to the unbound form. In the induced-fit hypothesis, the ligand induces the protein to explore regions of the conformational space that are virtually inaccessible to the unbound form. Whereas direct observation of target dynamics has found a significant role for conformational selection, 9] induced-fit effects have been shown to be important in the binding pocket of a ionotropic glutamate receptor. The idea that both mechanisms play a role in ligand/target binding is gaining new ground. Similar to enzymatic catalysis, the interplay between the two mechanisms may be regulated by the different time scales that are involved and by allosteric effects. 13] Herein, we have tested the various hypotheses in the pharmacologically relevant case of the phosphoinositide 3-kinases (PI3K). We performed four long, all-atom molecular dynamics (MD) simulations (each lasting 1 ms or more), extensive bias-exchange metadynamics calculations, and analyzed the conformational space that is spanned by the available crystal structures. The finding that the PI3K-signaling pathway is often deregulated in cancer has fueled an increasing interest in designing selective and potent inhibitors of PI3K kinases 16] There are four different isoforms of class I PI3Ks. These isoforms have distinct substrate specificities and different roles in discrete cellular processes. Given their high sequence retention (95 % or more) and a nearly identical adenosine triphosphate (ATP) binding pocket, it is not surprising that a potent and selective inhibitor for only one of the isoforms had remained elusive for a long time. The first selective inhibitor for the delta isoform was reported in 2003. Recently, the crystal structures of various PI3K isoforms in complexes with different inhibitors were published. These structures showed a significant conformational variability in the binding cavity. This variability is particularly prominent in the oncogenic target PI3K-g, which makes it a valid and interesting system with which to explore conformational selection versus the induced-fit hypothesis (Figure 1; see also Figures S1 and S2 in the Supporting Information). We explored the conformational space of the apo form (1E8Y) and the L64cocrystallized holo form (3IBE) of PI3K-g by performing two fully solvated MD simulations that lasted 1.5 ms and 1 ms, respectively. The dynamics were analyzed by principal component analysis (PCA) of the full MD trajectory and considered first the C a coordinates, and then only the atoms defining the binding pocket (Table S2 in the Supporting Information). The global C a PCA vectors of the apo and the holo forms are similar, as shown by the overlap of their covariance matrices (ca. 0.4). The first two vectors describe functionally relevant, hinge-like motions and the relative rotations of the N-terminal and C-terminal lobe. The local binding pocket vectors describe the opening and closing of the cavity (Figure S3 in the Supporting Information), but the overlap of the covariance matrices of the apo and the holo forms is smaller (ca. 0.2). The free energy surfaces (FESs) shown in Figure 2 are obtained by projecting MD trajectories of the apo form (Figure 2a, b) and the holo form (Figure 2c,d) on the first two C a coordinates and binding pocket vectors of the apo-form trajectory. The convergence of the FESs of the apo form and the effect of the initial structure was checked by performing an additional 1 ms long MD simulation. This simulation started from a different crystal structure (3DBS) after the removal of the GD9 ligand, and the new FES was compared with the [*] Dr. M. D’Abramo, Dr. F. L. Gervasio Structural Biology and Biocomputing Programme Spanish National Cancer Research Center (CNIO) C/Melchor Fernandez Almagro 3, 28029 Madrid (Spain) E-mail: flgervasio@cnio.es

Identification of ETP-46321, a potent and orally bioavailable PI3K α, δ inhibitor.

Phosphoinositide-3-kinase (PI3K) is an important target for cancer therapeutics due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein, we describe the optimization of imidazo [1,2-a] pyrazines, which allow us to identify compound 14 (ETP-46321), with potent biochemical and cellular activity and good pharmacokinetic properties (PK) after oral dosing. ETP-46321 PK/PD studies showed time dependent downregulation of AKT(Ser473) phosphorylation, which correlates with compound levels in tumor tissue and demonstrating to be efficacious in a GEMM mouse tumor model driven by a K-Ras(G12V) oncogenic mutation. Treatment with ETP-46321 resulted in significant tumor growth inhibition.

Computational medicinal chemistry in fragment-based drug discovery: what, how and when

The use of fragment-based drug discovery (FBDD) has increased in the last decade due to the encouraging results obtained to date. In this scenario, computational approaches, together with experimental information, play an important role to guide and speed up the process. By default, FBDD is generally considered as a constructive approach. However, such additive behavior is not always present, therefore, simple fragment maturation will not always deliver the expected results. In this review, computational approaches utilized in FBDD are reported together with real case studies, where applicability domains are exemplified, in order to analyze them, and then, maximize their performance and reliability. Thus, a proper use of these computational tools can minimize misleading conclusions, keeping the credit on FBDD strategy, as well as achieve higher impact in the drug-discovery process. FBDD goes one step beyond a simple constructive approach. A broad set of computational tools: docking, R group quantitative structure-activity relationship, fragmentation tools, fragments management tools, patents analysis and fragment-hopping, for example, can be utilized in FBDD, providing a clear positive impact if they are utilized in the proper scenario - what, how and when. An initial assessment of additive/non-additive behavior is a critical point to define the most convenient approach for fragments elaboration.