Polypharmacology Modelling Using Proteochemometrics (PCM): Recent Methodological Developments, Applications to Target Families, and Future Prospects

Peer reviewe

Artificial intelligence in biological activity prediction

Artificial intelligence has become an indispensable resource in chemoinformatics. Numerous machine learning algorithms for activity prediction recently emerged, becoming an indispensable approach to mine chemical information from large compound datasets. These approaches enable the automation of compound discovery to find biologically active molecules with important properties. Here, we present a review of some of the main machine learning studies in biological activity prediction of compounds, in particular for sweetness prediction. We discuss some of the most used compound featurization techniques and the major databases of chemical compounds relevant to these tasks.This study was supported by the European Commission through project SHIKIFACTORY100 - Modular cell factories for the production of 100 compounds from the shikimate pathway (Reference 814408), and by the Portuguese FCT under the scope of the strategic funding of UID/BIO/04469/2019 unit and BioTecNorte operation (NORTE-01-0145-FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020.info:eu-repo/semantics/publishedVersio

Improving virtual screening of G protein-coupled receptors via ligand-directed modeling

G protein-coupled receptors (GPCRs) play crucial roles in cell physiology and pathophysiology. There is increasing interest in using structural information for virtual screening (VS) of libraries and for structure-based drug design to identify novel agonist or antagonist leads. However, the sparse availability of experimentally determined GPCR/ligand complex structures with diverse ligands impedes the application of structure-based drug design (SBDD) programs directed to identifying new molecules with a select pharmacology. In this study, we apply ligand-directed modeling (LDM) to available GPCR X-ray structures to improve VS performance and selectivity towards molecules of specific pharmacological profile. The described method refines a GPCR binding pocket conformation using a single known ligand for that GPCR. The LDM method is a computationally efficient, iterative workflow consisting of protein sampling and ligand docking. We developed an extensive benchmark comparing LDM-refined binding pockets to GPCR X-ray crystal structures across seven different GPCRs bound to a range of ligands of different chemotypes and pharmacological profiles. LDM-refined models showed improvement in VS performance over origin X-ray crystal structures in 21 out of 24 cases. In all cases, the LDM-refined models had superior performance in enriching for the chemotype of the refinement ligand. This likely contributes to the LDM success in all cases of inhibitor-bound to agonist-bound binding pocket refinement, a key task for GPCR SBDD programs. Indeed, agonist ligands are required for a plethora of GPCRs for therapeutic intervention, however GPCR X-ray structures are mostly restricted to their inactive inhibitor-bound state

Research on pathogens in dairy goat and dairy sheep farms

Dieren kunnen verwekkers van ziekten bij zich dragen die op mensen kunnen worden overgebracht (zoönosen). In 2016 hebben het RIVM en de NVWA onderzocht of melkgeiten en melkschapen zulke ziekteverwekkers bij zich dragen; soms is dat ook bij veehouders, gezinsleden en medewerkers gedaan. Deze ziekteverwekkers veroorzaken meestal diarree maar soms kunnen de infecties ook ernstiger verlopen. Uit het onderzoek blijkt dat een paar ziekteverwekkers vaak op melkgeiten- en melkschapenbedrijven voorkomen. De gevonden bacteriën zitten in de darmen van de dieren en komen zo in de mest terecht. Een kleine hoeveelheid mest kan rauw te drinken melk of rauwmelkse kaas al besmetten. Daarnaast kunnen bezoekers van deze bedrijven besmet raken als zij contact hebben met de dieren of hun omgeving. Een besmetting kan worden voorkomen door alle melk gepasteuriseerd te consumeren of te verwerken. Bezoekers kunnen de kans op ziekte verkleinen door hun handen te wassen als ze in contact zijn geweest met de dieren of hun omgeving. Vooral de bacteriën STEC en Campylobacter zijn in hoge mate aangetroffen. STEC kwam op vrijwel alle onderzochte bedrijven voor. Campylobacter is aangetoond op 33 procent van de geiten- en op 95,8 procent van de schapenbedrijven. Bij de veehouders en gezinsleden zijn deze bacteriën veel minder gevonden. Listeria kwam in mindere mate voor? op 8,8 procent van de geiten- en 16,7 procent van de schapenbedrijven, en niet bij de mensen. Het is wel een relevante ziekteverwekker omdat rauwmelkse zachte kaas hiervoor de belangrijkste infectiebron voor mensen is. Salmonella werd niet gevonden op melkgeitenbedrijven, maar wel op 12,5 procent van de melkschapenbedrijven. Op de meeste bedrijven werd alleen een type Salmonella gevonden dat niet overgedragen wordt op de mens. ESBL-producerende bacteriën, die ongevoelig zijn voor veel antibiotica, werden aangetoond op 1,7 procent van de geitenbedrijven en 4,2 procent van de schapenbedrijven. Daarnaast werd hij bij 6,8 procent van de mensen aangetroffen. Dit percentage is niet hoger dan bij de algemene bevolking.Animals can carry pathogens that can cause disease in humans (zoonoses). In 2016, the RIVM and the NVWA investigated whether dairy goats and dairy sheep carry such pathogens; sometimes this is also done for livestock farmers, their family members and employees. These pathogens usually cause diarrhoea but sometimes the infections are more severe. Research shows that a few pathogens occur often on dairy goat and dairy sheep farms. These bacteria reside in the intestines of the animals, and are excreted in manure. A small amount of manure is enough to contaminate raw milk or unpasteurised cheese. Visitors to these farms can also become infected if they come into contact with the animals or their environment. Contamination can be prevented by consuming or processing all milk pasteurized. Visitors can reduce the risk of disease by washing their hands if they have been in contact with the animals or their environment. STEC and Campylobacter bacteria, in particular, were frequently found. STEC was detected at virtually all the farms that were investigated. Campylobacter was detected at 33 percent of the goat farms and 95.8 percent of the sheep farms. These bacteria were found much less often among the farmers and their family members. Listeria was detected less often: at 8.8 percent of the goat farms and 16.7 percent of the sheep farms, and not among people. However, it is a relevant pathogen since unpasteurised soft cheese is the most important source of Listeria infection in humans. Salmonella was not found at dairy goat farms but was found at 12.5 percent of the dairy sheep farms. On most farms, only a type of Salmonella that is not transmitted to humans was found. ESBL-producing bacteria, which are insensitive to many antibiotics, were detected at 1.7 percent of the goat farms and 4.2 percent of the sheep farms. They were also found in 6.8 percent of the people. This percentage is not higher than for the general population.NVW

Surveillance zoönosen in de melkgeiten- en melkschapenhouderij in 2016

Dieren kunnen verwekkers van ziekten bij zich dragen die op mensen kunnen worden overgebracht (zoönosen). In 2016 hebben het RIVM en de NVWA onderzocht of melkgeiten en melkschapen zulke ziekteverwekkers bij zich dragen; soms is dat ook bij veehouders, gezinsleden en medewerkers gedaan. Deze ziekteverwekkers veroorzaken meestal diarree maar soms kunnen de infecties ook ernstiger verlopen. Uit het onderzoek blijkt dat een paar ziekteverwekkers vaak op melkgeiten- en melkschapenbedrijven voorkomen. De gevonden bacteriën zitten in de darmen van de dieren en komen zo in de mest terecht. Een kleine hoeveelheid mest kan rauw te drinken melk of rauwmelkse kaas al besmetten. Daarnaast kunnen bezoekers van deze bedrijven besmet raken als zij contact hebben met de dieren of hun omgeving. Een besmetting kan worden voorkomen door alle melk gepasteuriseerd te consumeren of te verwerken. Bezoekers kunnen de kans op ziekte verkleinen door hun handen te wassen als ze in contact zijn geweest met de dieren of hun omgeving. Vooral de bacteriën STEC en Campylobacter zijn in hoge mate aangetroffen. STEC kwam op vrijwel alle onderzochte bedrijven voor. Campylobacter is aangetoond op 33 procent van de geiten- en op 95,8 procent van de schapenbedrijven. Bij de veehouders en gezinsleden zijn deze bacteriën veel minder gevonden. Listeria kwam in mindere mate voor? op 8,8 procent van de geiten- en 16,7 procent van de schapenbedrijven, en niet bij de mensen. Het is wel een relevante ziekteverwekker omdat rauwmelkse zachte kaas hiervoor de belangrijkste infectiebron voor mensen is. Salmonella werd niet gevonden op melkgeitenbedrijven, maar wel op 12,5 procent van de melkschapenbedrijven. Op de meeste bedrijven werd alleen een type Salmonella gevonden dat niet overgedragen wordt op de mens. ESBL-producerende bacteriën, die ongevoelig zijn voor veel antibiotica, werden aangetoond op 1,7 procent van de geitenbedrijven en 4,2 procent van de schapenbedrijven. Daarnaast werd hij bij 6,8 procent van de mensen aangetroffen. Dit percentage is niet hoger dan bij de algemene bevolking

Population- and type-specific clustering of multiple HPV types across diverse risk populations in the Netherlands

In view of possible type replacement upon introduction of human papillomavirus (HPV) vaccination, we aimed to explore patterns of type-specific clustering across populations with various background infection risks. A total of 3,874 women from 3 cross-sectional studies in the Netherlands (in 2007-2009) provided vaginal self-samples, which were tested for 25 HPV genotypes by a sensitive molecular assay (SPF10 line probe assay, DDL Diagnostic Laboratory, Voorburg, the Netherlands). The number of concurrent HPV infections per woman was studied by Poisson regression. Associations between HPV types were investigated by generalized estimating equation analyses. The prevalence of any HPV type was 14% in a population-based study, 54% in a chlamydia screening intervention study, and 73% in a study among attendees of sexually transmitted infection clinics. Overall, multiple HPV infections were detected in 26% of the women. The number of concurrent HPV infections conformed to an overdispersed Poisson distribution, even after correction for known risk factors. Types differed significantly in their tendencies to be involved in coinfections, but no evidence for particular type-type interactions was found. Moreover, the strongest associations were observed in the lowest-risk population and vice versa.We found no indications of pairwise interactions, but our findings do suggest that clustering differs among HPV types and varies across risk group

Microbially mediated carbonates in the Holocene deposits from Sarliève, a small ancient lake of the French Massif Central, testify to the evolution of a restricted environment

International audienceBoth the mineralogy and facies of lacustrine bio-induced carbonates are controlled largely by hydrological factors that are highly dependent upon climatic influence. As such they are useful tools in characterizing ancient lake environments. In this way, the study of the sedimentary record from the small ancient Sarlie've Lake (Limagne, Massif Central, France) aims to reconstruct the hydrological evolution during the Holocene, using petrographical, mineralogical and geochemical analyses. The fine-grained marls, mainly calcitic, display numerous layers rich in pristine Ca-dolomite, with small amounts of aragonite, which are clearly utochthonous. As these minerals are rather unusual in the temperate climatic context of western Europe, the question arises about their forming conditions, and therefore that of the lacustrine environment. Ca-dolomite prevails at the base of the sequence as a massive dolomicrite layer and, in the middle part, it builds up most of the numerous laminae closely associated with organic matter. Scanning electron microscope observations reveal the abundance of tiny crystals (tens to hundreds of nanometres) mainly organized as microspheres looking like cocci or bacilli. Such a facies is interpreted as resulting from the fossilization of benthic microbial communities by dolomite precipitation following organic matter consumption and extracellular polymeric substance degradation. These microbial dolomites were precipitated in a saline environment, as a consequence of excess evaporation from the system, as is also suggested by their positive ¶18O values. The facies sequence expresses the following evolution: (i) saline pan, i.e. endorheic stage with a perennial lowstand in lake level (Boreal to early Atlantic periods); (ii) large fluctuations in lake level with sporadic freshening of the system (Atlantic); (iii) open lake stage (sub-boreal); and (iv) anthropogenic drainage (sub-Atlantic)