Integrating virtual and high-throughput screening: opportunities and challenges in drug research and development

High-throughput screening (HTS) and virtual screening (VS) are useful methods employed in drug discovery, allowing the identification of promising hits for lead optimization. The efficiency of these approaches depends on a number of factors, such as the organization of high quality databases of compounds and the parameterization of essential components of the screen process. This brief review presents the basic principles of the HTS and VS methods, as well as a perspective of the utility and integration of these drug design approaches, highlighting current opportunities and future challenges in medicinal chemistry.FAPESPCNP

Environmental impact monitoring of a minero-chemical complex in Catalão urban area of PTS, PM10 and PM2.5 by EDX characterization

Depending on its nature, particulate matter has very different size, composition and morphology. By the combination of these criteria it is possible to distinguish the emitting sources (primary or secondary). The shape and the dimension of the particles have also a direct interaction with the risk assessment for human health. The minero-chemical complex consists of phosphate fertilizer manufacturing, rock phosphate and niobium mining open pits and it is located northeast of the urban area of the city. Environmental issues associated with it include the following: fugitive emissions which are primarily associated with operational leaks from tubing, valves, connections, flanges, packings, open ended lines, floating roof storage tank and pump seals, gas conveyance systems, compressor seals, pressure relief valves, tanks or open its/containments, and loading and unloading operations of products. Furthermore the area of study is characterized by a predominantly northeast winds direction. The monitoring was performed weekly particulates samples were collected in two seasonal episodes at one representative places in the urban area of Catalao (a Brazilian city located in Goias state) in the period from August to November of 2014. Suspended particles were sampled on pure fiberglass filters by using a High Volume air sampler and were analyzed via an energy dispersive X-ray microanalysis system (EDX). The airborne particulate matter was characterized from a physico-chemical point of view to supply information on the particle composition and the compounds carried on their surfaces. The microanalysis enables identification of several groups of particles such as: soot, Si-rich, metal-rich and biological particules. These results may help in controlling and preventing fugitive emissions in atmospheric air.Depending on its nature, particulate matter has very different size, composition and morphology. By the combination of these criteria it is possible to distinguish the emitting sources (primary or secondary). The shape and the dimension of the particles h4319091914CNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPEG - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE GOIÁSsem informaçãosem informaçãoFinancial support and scholarships from the Brazilian funding agencies CNPq, FAPEG and Environment Office City of Catalão, City Council Environmental Protection of Catalão and Public Ministry of Goiás State are gratefully acknowledged

Towards customized footwear with improved comfort

A methodology enabling the customization of shoes for comfort improvement is proposed and assessed. For this aim, 3D printed graded density inserts were placed in one of the critical plantar pressure zones of conventional insoles, the heel. A semi-automated routine was developed to design the 3D inserts ready for printing, which comprises three main stages: (i) the definition of the number of areas with different mesh density, (ii) the generation of 2D components with continuous graded mesh density, and (iii) the generation of a 3D component having the same 2D base mesh. The adequacy of the mesh densities used in the inserts was previously assessed through compression tests, using uniform mesh density samples. Slippers with different pairs of inserts embedded in their insoles were mechanically characterized, and their comfort was qualitatively assessed by a panel of users. All users found a particular pair, or a set, of prototype slippers more comfortable than the original ones, taken as reference, but their preferences were not consensual. This emphasizes the need for shoe customization, and the usefulness of the proposed methodology to achieve such a goal.This work was funded by National Funds through FCT—Portuguese Foundation for Science and Technology, Reference UID/CTM/50025/2019 and UIDB/04436/2020, and Project FAMEST, Reference POCI-01-0247-FEDER-024529, co-financed by COMPETE2020 through PT2020 and FEDER

In silico screening strategies for novel inhibitors of parasitic diseases

Introduction: Parasitic diseases are a major global problem causing long-term disability and death, with severe medical and psychological consequences around the world. Despite the prevalence of parasitic disease, the treatment options for many of these illnesses are still inadequate and there is a dire need for new antiparasitic drugs. In silico screening techniques, which are powerful strategies for hit generation, are widely being applied in the design of new ligands for parasitic diseases.\ud Areas covered: This article analyses the application of ligand- and structure-based virtual screening strategies against a variety of parasitic diseases and discusses the benefits of the integration between computational and experimental approaches toward the discovery of new antiparasitic agents. The analysis is illustrated by recent examples, with emphasis on the strategies reported within the past 2 years.\ud Expert opinion: Virtual screening techniques are powerful tools commonly used in drug discovery against parasitic diseases, which have provided new opportunities for the identification of several novel compound classes with antiparasitic activity

Cutting Forces Assessment in CNC Machining Processes: A Critical Review

Machining processes remain an unavoidable technique in the production of high-precision parts. Tool behavior is of the utmost importance in machining productivity and costs. Tool performance can be assessed by the roughness left on the machined surfaces, as well as of the forces developed during the process. There are various techniques to determine these cutting forces, such as cutting force prediction or measurement, using dynamometers and other sensor systems. This technique has often been used by numerous researchers in this area. This paper aims to give a review of the different techniques and devices for measuring the forces developed for machining processes, allowing a quick perception of the advantages and limitations of each technique, through the literature research carried out, using recently published worksThe present work was done and funded under the scope of the project ON-SURF (ANI | P2020 | POCI-01-0247-FEDER-024521, co-funded by Portugal 2020 and FEDER, through COMPETE 2020-Operational Programme for Competitiveness and Internationalisation. F.J.G. Silva also thanks INEGI-Instituto de Ciência e Inovação em Engenharia Mecânica e Engenharia Industria, due to its support.info:eu-repo/semantics/publishedVersio

What is the response profile of deciduous pulp fibroblasts stimulated with E. coli LPS and E. faecalis LTA?

BACKGROUND: Oral fibroblast immunological responses to bacterial stimuli are well known. However, there are few studies about pulp fibroblasts from deciduous teeth (HDPF) responses, which are important for the treatment of pulp infections in children. The aim of this study was to evaluate expression and production of inflammatory cytokines and chemokines by HDPF when challenged with bacterial antigens normally present in advanced caries lesions. METHODS: Triplicate HDPF from 4 children (n = 4; 2 boys and 2 girls) were cultured by explant technique and challenged or not with Escherichia coli lipopolysaccharide/1 μg/mL (EcLPS) or Enterococcus faecalis lipoteichoic acid/1 μg/mL (EfLTA) for 6 and 24 h. Most of published studies employed immortalized cells, i.e., without checking possible gender and genetic variables. mRNA expression and protein production were evaluated by RT-qPCR and ELISA MILLIPLEX®, respectively, for Interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, Chemokine C-C motif ligand 2/monocyte chemoattractant protein 1 (CCL2/MCP-1), Chemokine C-C motif ligand 3/macrophage inflammatory protein 1-alpha (CCL3/MIP1-α), Chemokine C-C motif ligand 5/ regulated on activation, normal T cell expressed and secreted (CCL5/RANTES), C-X-C motif chemokine 12/ stromal cell-derived factor 1 (CXCL12/SDF-1), Tumor Necrosis Factor-alpha (TNF-α), Interferon-gamma (IFN γ), Vascular Endothelial Growth Factor (VEGF), Colony stimulating factor 1 (CSF-1) and Macrophage colony-stimulating factor (M-CSF). RESULTS: EcLPS increased IL-1α, IL-1β, IL-8, CCL2, CCL5, TNF-α and CSF-1 mRNA and protein levels while EfLTA was only able to positively regulate gene expression and protein production of IL-8. CONCLUSION: The results of the present study confirmed our hypothesis, since pulp fibroblasts from deciduous teeth are capable of increasing gene expression and protein production after being stimulated with EcLPS and EfLTA

It Takes Two to Tango, Part II : Synthesis of A-Ring Functionalised Quinones Containing Two Redox-Active Centres with Antitumour Activities

In 2021, our research group published the prominent anticancer activity achieved through the successful combination of two redox centres (ortho-quinone/para-quinone or quinone/seleniumcontaining triazole) through a copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The combination of two naphthoquinoidal substrates towards a synergetic product was indicated, but not fully explored. Herein, we report the synthesis of 15 new quinone-based derivatives prepared from click chemistry reactions and their subsequent evaluation against nine cancer cell lines and the murine fibroblast line L929. Our strategy was based on the modification of the A-ring of paranaphthoquinones and subsequent conjugation with different ortho-quinoidal moieties. As anticipated, our study identified several compounds with IC50 values below 0.5 µM in tumour cell lines. Some of the compounds described here also exhibited an excellent selectivity index and low cytotoxicity on L929, the control cell line. The antitumour evaluation of the compounds separately and in their conjugated form proved that the activity is strongly enhanced in the derivatives containing two redox centres. Thus, our study confirms the efficiency of using A-ring functionalized para-quinones coupled with ortho-quinones to obtain a diverse range of two redox centre compounds with potential applications against cancer cell lines. Here as well, it literally takes two for an efficient tango

The Halogen Effect on the Magnetic Behaviour of Dimethylformamide Solvates in [Fe(halide-salEen)2]BPh4

Funding Research was funded by Fundação para a Ciência e a Tecnologia (FCT): projects UIDB/00100/2020, UIDP/00100/2020, LA/P/0056/2020, UIDB/04046/2020, UIDP/04046/2020, UIDB/50006/2020, UIDP/50006/2020 and LA/P/0008/2020, UIDB/04378/2020, UIDP/04378/2020, and LA/P/0140/2020, PTDC/QUI-QFI/29236/2017, PTDCQUI-QIN0252_2021, CEECIND/00509/2017; Fonds de la Recherche Scientifique (FNRS): PDR T.0095.21); Portugal2020: CENTRO-01-0145-FEDER-000018; Royal Society of Chemistry (RSC): R21-7511142525. Acknowledgments Centro de Química Estrutural (CQE) and Institute of Molecular Sciences (IMS) acknowledge the financial support of Fundação para a Ciência e a Tecnologia (FCT): Projects UIDB/00100/2020, UIDP/00100/2020, and LA/P/0056/2020, respectively. BioISI acknowledges FCT for financial support (UIDB/04046/2020, UIDP/04046/2020). This work was supported by the FNRS (PDR T.0095.21). Clara S. B. Gomes acknowledges the Associate Laboratory for Green Chemistry—LAQV, the Applied Molecular Biosciences Unit—UCIBIO and Associated Laboratory i4HB, which are financed by national funds from FCT (UIDB/50006/2020, UIDP/50006/2020 and LA/P/0008/2020, UIDB/04378/2020 and UIDP/04378/2020, and LA/P/0140/2020, respectively). Sónia Barroso thanks project SmartBioR for financial support (CENTRO-01-0145-FEDER-000018)and Centro de Química Estrutural for the access to crystallography facilities. Nuno A. G. Bandeira gratefully acknowledges the NanoBioSolutions FCT grant PTDC/QUI-QFI/29236/2017 for the computational infrastructure. Paulo N. Martinho thanks FCT and RSC for financial support (grants PTDCQUI-QIN0252_2021 and R21-7511142525). Paulo N. Martinho also thanks FCT for the contract CEECIND/00509/2017.Complexes [Fe(X-salEen)2]BPh4·DMF, with X = Br (1), Cl (2), and F (3), were crystallised from N,N′-dimethylformamide with the aim of understanding the role of a high boiling point N,N′-dimethylformamide solvate in the spin crossover phenomenon. The counter ion was chosen for only being able to participate in weak intermolecular interactions. The compounds were structurally characterised by single crystal X-ray diffraction. Complex 1 crystallised in the orthorhombic space group P212121, and complexes 2 and 3 in the monoclinic space group P21/n. Even at room temperature, low spin was the predominant form, although complex 2 exhibited the largest proportion of the high-spin species according to both the magnetisation measurements and the Mössbauer spectra. Density Functional Theory calculations were performed both on the periodic solids and on molecular models for complexes 1–3 and the iodide analogue 4. While all approaches reproduced the experimental structures very well, the energy balance between the high-spin and low-spin forms was harder to reproduce, though some calculations pointed to the easier spin crossover of complex 2, as observed. Periodic calculations with the functional PBE led to very similar ΔEHS-LS values for all complexes but showed a preference for the low-spin form. However, the single-point calculations with B3LYP* showed, for the model without solvate, that the Cl complex should undergo spin crossover more easily. The molecular calculations also reflected this fact, which was more clearly defined when the cation–anion–solvate model was used. In the other models there was not much difference between the Cl, Br, and I complexes.publishersversionpublishe