Data-driven approaches used for compound library design, hit triage and bioactivity modeling in high-throughput screening

High-throughput screening (HTS) campaigns are routinely performed in pharmaceutical companies to explore activity profiles of chemical libraries for the identification of promising candidates for further investigation. With the aim of improving hit rates in these campaigns, data-driven approaches have been used to design relevant compound screening collections, enable effective hit triage and perform activity modeling for compound prioritization. Remarkable progress has been made in the activity modeling area since the recent introduction of large-scale bioactivity-based compound similarity metrics. This is evidenced by increased hit rates in iterative screening strategies and novel insights into compound mode of action obtained through activity modeling. Here, we provide an overview of the developments in data-driven approaches, elaborate on novel activity modeling techniques and screening paradigms explored and outline their significance in HTS.Medicinal Chemistr

Analyzing multitarget activity landscapes using protein-ligand interaction fingerprints: interaction cliffs.

This is the original submitted version, before peer review. The final peer-reviewed version is available from ACS at http://pubs.acs.org/doi/abs/10.1021/ci500721x.Activity landscape modeling is mostly a descriptive technique that allows rationalizing continuous and discontinuous SARs. Nevertheless, the interpretation of some landscape features, especially of activity cliffs, is not straightforward. As the nature of activity cliffs depends on the ligand and the target, information regarding both should be included in the analysis. A specific way to include this information is using protein-ligand interaction fingerprints (IFPs). In this paper we report the activity landscape modeling of 507 ligand-kinase complexes (from the KLIFS database) including IFP, which facilitates the analysis and interpretation of activity cliffs. Here we introduce the structure-activity-interaction similarity (SAIS) maps that incorporate information on ligand-target contact similarity. We also introduce the concept of interaction cliffs defined as ligand-target complexes with high structural and interaction similarity but have a large potency difference of the ligands. Moreover, the information retrieved regarding the specific interaction allowed the identification of activity cliff hot spots, which help to rationalize activity cliffs from the target point of view. In general, the information provided by IFPs provides a structure-based understanding of some activity landscape features. This paper shows examples of analyses that can be carried out when IFPs are added to the activity landscape model.M-L is very grateful to CONACyT (No. 217442/312933) and the Cambridge Overseas Trust for funding. AB thanks Unilever for funding and the European Research Council for a Starting Grant (ERC-2013- StG-336159 MIXTURE). J.L.M-F. is grateful to the School of Chemistry, Department of Pharmacy of the National Autonomous University of Mexico (UNAM) for support. This work was supported by a scholarship from the Secretariat of Public Education and the Mexican government

Volviéndonos mejores: necesidad de acción inmediata ante el reto de la obesidad. Una postura de profesionales de la salud.

La creciente epidemia de obesidad ha sido uno de los retos más importantes de salud pública en México durante los últimos años. Con apoyo de la Federación Mundial de Obesidad, en 2021 formamos un grupo de profesionales para identificar y resumir las acciones prioritarias en las que puede enfocarse nuestro país para hacer frente a esta epidemia. Al proceso de desarrollo y discusión de este grupo se sumaron más de 1 000 profesionales de la salud para retomar recomendaciones de documentos y guías de alto nivel previamente publicados. En conmemoración del Día Mundial de la Obesidad, en este 2022 se presenta esta postura como insumo para el desarrollo de acciones en el ámbito profesional y de los diferentes sectores, en la que se incluyen 10 recomendaciones de acción, desde la perspectiva poblacional hasta la atención individualizada, y se enfatiza en la importancia de la participación social, de las intervenciones integrales con visión centrada en la persona y de la sostenibilidad planetaria, además de mejorar la educación y las campañas de difusión, propiciar un ambiente promotor de entornos activos y blindar de conflictos de interés los esfuerzos de prevención y control. La postura hace un llamado para abordar la obesidad de manera seria, con base en la evidencia científica, oportuna e integral, con enfoque de curso de vida, de forma ética y sensible, y sin perpetuar las barreras del estigma de peso en la sociedad

Reaction production + AMS: An alternative method to study low energy reactions.

Considering the importance of the 26Al nuclei in Astrophysics, in this work, preliminary results regarding a campaign of measurements related with this radioisotope production, are presented. We have taken advantage of two different facilities: first, the radio-nucleus is produced by means of irradiation of targets selected in correlation with particular reactions; once the enrichment with 26Al was made, the targets are analyzed in an AMS machine to obtain the concentration of 26Al produced during the irradiation. With this off-line method, it is possible to measure acceptable small cross sections of a selected low energy reaction. In this work, our preliminary results for three different energies of 28Si(d,α)26Al reaction cross sections are shown, as well as our first considerations to commence with measurements of 25Mg(p,γ)26Al reaction cross sections below 1 MeV

Reaction production + AMS: An alternative method to study low energy reactions. 26Al as a test case

Considering the importance of the 26Al nuclei in Astrophysics, in this work, preliminary results regarding a campaign of measurements related with this radioisotope production, are presented. We have taken advantage of two different facilities: first, the radio-nucleus is produced by means of irradiation of targets selected in correlation with particular reactions; once the enrichment with 26Al was made, the targets are analyzed in an AMS machine to obtain the concentration of 26Al produced during the irradiation. With this off-line method, it is possible to measure acceptable small cross sections of a selected low energy reaction. In this work, our preliminary results for three different energies of 28Si(d,α)26Al reaction cross sections are shown, as well as our first considerations to commence with measurements of 25Mg(p,γ)26Al reaction cross sections below 1 MeV

The Current Molecular Epidemiological Scenario of Cryptosporidium, Giardia and Blastocystis in Spain. Implication for Public Health

The enteric protozoan parasites Cryptosporidium spp. and Giardia duodenalis are major contributors to the burden of gastrointestinal diseases globally. Both pathogens primarily affect children living in resource-poor settings with limited or no access to clean water and sanitation facilities, but are also significant public health threats in developed countries. Additionally, Cryptosporidium spp. and G. duodenalis are common causes of waterborne and foodborne outbreaks of gastrointestinal disease globally. Besides, the Stramenopile Blastocystis sp. is the most common eukaryotic organism reported in the human gut. Although its pathogenicity is a topic of debate, there is increasing evidence demonstrating that this protist can be associated with gastrointestinal disorders (diarrhoea, irritable bowel syndrome) and extra-intestinal manifestations, including urticaria. Because Cryptosporidium spp., G. duodenalis and Blastocystis sp. share the same transmission (faecal-oral) route, are able to infect a wide range of animal species other than humans with variable host specificities, and their infective forms are environmentally resilient, the study of these pathogens should be ideally approached under the One Health umbrella. In this context, molecular-based methods including PCR and sequencing provide powerful tools to investigate the epidemiology and transmission of these parasites. In Spain, cryptosporidiosis and giardiosis, but not blastocystosis, are notifiable diseases. However, the true incidence of these infections remain largely unknown because underdiagnosing and underreporting. Symptomatic cryptosporidiosis and giardiosis disproportionally affect children under four years of age, but we know now that subclinical infections are also common in apparently healthy individuals of all age groups. However, molecular data regarding the frequency and diversity of these pathogens are limited and spatially and temporally discontinuous. This chapter aims to provide, from a public veterinary health perspective, an updated account on the epidemiology of Cryptosporidium, G. duodenalis and Blastocystis in Spain, with an emphasis on the description of the species/genotypes circulating in symptomatic and asymptomatic human populations. Current knowledge on the presence of these pathogens in production (livestock), companion (dogs and cats) and wildlife animal species is also discussed, including their potential role as natural reservoirs of human infections, and the available evidence of zoonotic (and anthroponotic) transmission events.Research summarized in this chapter and conducted at the Spanish National Centre for Microbiology was funded by the Health Institute Carlos III (ISCIII), Ministry of Economy and Competitiveness (Spain), under projects CP12/03081 and PI16CIII/00024. The funder had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.S

Epigenetic polypharmacology: a new frontier for epi-drug discovery

Recently, despite the great success achieved by the so-called "magic bullets" in the treatment of different diseases through a marked and specific interaction with the target of interest, the pharmacological research is moving toward the development of "molecular network active compounds," embracing the related polypharmacology approach. This strategy was born to overcome the main limitations of the single target therapy leading to a superior therapeutic effect, a decrease of adverse reactions, and a reduction of potential mechanism(s) of drug resistance caused by robustness and redundancy of biological pathways. It has become clear that multifactorial diseases such as cancer, neurological, and inflammatory disorders, may require more complex therapeutic approaches hitting a certain biological system as a whole. Concerning epigenetics, the goal of the multi-epi-target approach consists in the development of small molecules able to simultaneously and (often) reversibly bind different specific epi-targets. To date, two dual histone deacetylase/kinase inhibitors (CUDC-101 and CUDC-907) are in an advanced stage of clinical trials. In the last years, the growing interest in polypharmacology encouraged the publication of high-quality reviews on combination therapy and hybrid molecules. Hence, to update the state-of-the-art of these therapeutic approaches avoiding redundancy, herein we focused only on multiple medication therapies and multitargeting compounds exploiting epigenetic plus nonepigenetic drugs reported in the literature in 2018. In addition, all the multi-epi-target inhibitors known in literature so far, hitting two or more epigenetic targets, have been included