Utilization of Additive Manufacturing Techniques for the Development of a Novel Scaffolds with Magnetic Properties for Potential Application in Enhanced Bone Regeneration.

This study focuses on designing and evaluating scaffolds with essential properties for bone regeneration, such as biocompatibility, macroporous geometry, mechanical strength, and magnetic responsiveness. The scaffolds are made using 3D printing with acrylic resin and iron oxides synthesized through solution combustion. Utilizing triply periodic minimal surfaces (TPMS) geometry and mask stereolithography (MSLA) printing, the scaffolds achieve precise geometrical features. The mechanical properties are enhanced through resin curing, and magnetite particles from synthesized nanoparticles and alluvial magnetite are added for magnetic properties. The scaffolds show a balance between stiffness, porosity, and magnetic responsiveness, with maximum compression strength between 4.8 and 9.2 MPa and Young's modulus between 58 and 174 MPa. Magnetic properties such as magnetic coercivity, remanence, and saturation are measured, with the best results from scaffolds containing synthetic iron oxides at 1% weight. The viscosity of the mixtures used for printing is between 350 and 380 mPas, and contact angles between 90° and 110° are achieved. Biocompatibility tests indicate the potential for clinical trials, though further research is needed to understand the impact of magnetic properties on cellular interactions and optimize scaffold design for specific applications. This integrated approach offers a promising avenue for the development of advanced materials capable of promoting enhanced bone regeneration.

Identification of Active Compounds against Melanoma Growth by Virtual Screening for Non-Classical Human DHFR Inhibitors.

Antifolates such as methotrexate (MTX) have been largely known as anticancer agents because of their role in blocking nucleic acid synthesis and cell proliferation. Their mechanism of action lies in their ability to inhibit enzymes involved in the folic acid cycle, especially human dihydrofolate reductase (hDHFR). However, most of them have a classical structure that has proven ineffective against melanoma, and, therefore, inhibitors with a non-classical lipophilic structure are increasingly becoming an attractive alternative to circumvent this clinical resistance. In this study, we conducted a protocol combining virtual screening (VS) and cell-based assays to identify new potential non-classical hDHFR inhibitors. Among 173 hit compounds identified (average logP = 3.68; average MW = 378.34 Da), two-herein, called C1 and C2-exhibited activity against melanoma cell lines B16 and A375 by MTT and Trypan-Blue assays. C1 showed cell growth arrest (39% and 56%) and C2 showed potent cytotoxic activity (77% and 51%) in a dose-dependent manner. The effects of C2 on A375 cell viability were greater than MTX (98% vs 60%) at equivalent concentrations and times. Our results indicate that the integrated in silico/in vitro approach provided a benchmark to identify novel promising non-classical DHFR inhibitors showing activity against melanoma cells.

Non-Nucleoside Lycorine-Based Analogs as Potential DENV/ZIKV NS5 Dual Inhibitors: Structure-Based Virtual Screening and Chemoinformatic Analysis.

Dengue (DENV) and Zika (ZIKV) virus continue to pose significant challenges globally due to their widespread prevalence and severe health implications. Given the absence of effective vaccines and specific therapeutics, targeting the highly conserved NS5 RNA-dependent RNA polymerase (RdRp) domain has emerged as a promising strategy. However, limited efforts have been made to develop inhibitors for this crucial target. In this study, we employed an integrated in silico approach utilizing combinatorial chemistry, docking, molecular dynamics simulations, MM/GBSA, and ADMET studies to target the allosteric N-pocket of DENV3-RdRp and ZIKV-RdRp. Using this methodology, we designed lycorine analogs with natural S-enantiomers (LYCS) and R-enantiomers (LYCR) as potential inhibitors of non-structural protein 5 (NS5) in DENV3 and ZIKV. Notably, 12 lycorine analogs displayed a robust binding free energy (<-9.00 kcal/mol), surpassing that of RdRp-ribavirin (<-7.00 kcal/mol) along with promising ADMET score predictions (<4.00), of which (LYCR728-210, LYCS728-210, LYCR728-212, LYCS505-214) displayed binding properties to both DENV3 and ZIKV targets. Our research highlights the potential of non-nucleoside lycorine-based analogs with different enantiomers that may present different or even completely opposite metabolic, toxicological, and pharmacological profiles as promising candidates for inhibiting NS5-RdRp in ZIKV and DENV3, paving the way for further exploration for the development of effective antiviral agents.

Classical MD and metadynamics simulations on back-pocket binders of CDK2 and VEGFR2: a guidepost to design novel small-molecule dual inhibitors.

Cyclin-Dependent Kinase 2 (CDK2) and Vascular-Endothelial Growth Factor Receptor 2 (VEGFR2) are promising targets for the design of novel inhibitors in anticancer therapeutics. In a recent work, our group designed a set of potential dual inhibitors predicted to occupy an allosteric back pocket near the active site of both enzymes, but their dynamic and unbinding behavior was unclear. Here, we used molecular dynamics (MD) and metadynamics (meta-D) simulations to study two of these virtual candidates (herein called IQ2 and IQ3). Their binding mode was predicted to be similar to that observed in LQ5 and BAX, well-known back-pocket binders of CDK2 and VEGFR2, respectively, including H-bonding with critical residues such as Leu83/Cys113 and Asp145/Asp190 (but excepting H-bonding with Glu51/Glu111) in CDK2/VEGFR2, correspondingly. Likewise, while LQ5 and BAX unbound through the allosteric channel as expected for type-IIA inhibitors, IQ2 and IQ3 unbound via the ATP channel (except for CDK2-IQ2) as expected for type-I½A inhibitors. Interestingly, a C-C single/double bond difference between IQ2/IQ3, respectively, resulted associated with differences in the AS/T loop flexibility observed for CDK2. These insights will help developing scaffold modifications during an optimization stage, serving as a starting point to develop dual kinase inhibitors in challenging biological targets with a promising anticancer potential.Communicated by Ramaswamy H. Sarma.

Novel covalent and non-covalent complex-based pharmacophore models of SARS-CoV-2 main protease (Mpro) elucidated by microsecond MD simulations.

As the world enters its second year of the pandemic caused by SARS-CoV-2, intense efforts have been directed to develop an effective diagnosis, prevention, and treatment strategies. One promising drug target to design COVID-19 treatments is the SARS-CoV-2 Mpro. To date, a comparative understanding of Mpro dynamic stereoelectronic interactions with either covalent or non-covalent inhibitors (depending on their interaction with a pocket called S1' or oxyanion hole) has not been still achieved. In this study, we seek to fill this knowledge gap using a cascade in silico protocol of docking, molecular dynamics simulations, and MM/PBSA in order to elucidate pharmacophore models for both types of inhibitors. After docking and MD analysis, a set of complex-based pharmacophore models was elucidated for covalent and non-covalent categories making use of the residue bonding point feature. The highest ranked models exhibited ROC-AUC values of 0.93 and 0.73, respectively for each category. Interestingly, we observed that the active site region of Mpro protein-ligand complex undergoes large conformational changes, especially within the S2 and S4 subsites. The results reported in this article may be helpful in virtual screening (VS) campaigns to guide the design and discovery of novel small-molecule therapeutic agents against SARS-CoV-2 Mpro protein.

Non-Extensive Fragmentation of Natural Products and Pharmacophore-Based Virtual Screening as a Practical Approach to Identify Novel Promising Chemical Scaffolds.

Fragment-based drug design (FBDD) and pharmacophore modeling have proven to be efficient tools to discover novel drugs. However, these approaches may become limited if the collection of fragments is highly repetitive, poorly diverse, or excessively simple. In this article, combining pharmacophore modeling and a non-classical type of fragmentation (herein called non-extensive) to screen a natural product (NP) library may provide fragments predicted as potent, diverse, and developable. Initially, we applied retrosynthetic combinatorial analysis procedure (RECAP) rules in two versions, extensive and non-extensive, in order to deconstruct a virtual library of NPs formed by the databases Traditional Chinese Medicine (TCM), AfroDb (African Medicinal Plants database), NuBBE (Nuclei of Bioassays, Biosynthesis, and Ecophysiology of Natural Products), and UEFS (Universidade Estadual de Feira de Santana). We then developed a virtual screening (VS) using two groups of natural-product-derived fragments (extensive and non-extensive NPDFs) and two overlapping pharmacophore models for each of 20 different proteins of therapeutic interest. Molecular weight, lipophilicity, and molecular complexity were estimated and compared for both types of NPDFs (and their original NPs) before and after the VS proceedings. As a result, we found that non-extensive NPDFs exhibited a much higher number of chemical entities compared to extensive NPDFs (45,355 vs. 11,525 compounds), accounting for the larger part of the hits recovered and being far less repetitive than extensive NPDFs. The structural diversity of both types of NPDFs and the NPs was shown to diminish slightly after VS procedures. Finally, and most interestingly, the pharmacophore fit score of the non-extensive NPDFs proved to be not only higher, on average, than extensive NPDFs (56% of cases) but also higher than their original NPs (69% of cases) when all of them were also recognized as hits after the VS. The findings obtained in this study indicated that the proposed cascade approach was useful to enhance the probability of identifying innovative chemical scaffolds, which deserve further development to become drug-sized candidate compounds. We consider that the knowledge about the deconstruction degree required to produce NPDFs of interest represents a good starting point for eventual synthesis, characterization, and biological activity studies.

Discovery of new potential CDK2/VEGFR2 type II inhibitors by fragmentation and virtual screening of natural products.

Cyclin-Dependent Kinase 2 (CDK2) and Vascular Endothelial Growth Factor Receptor (VEGFR2) have largely been considered as attractive targets for developing anticancer agents. However, there is no dual inhibitor commercially available in the market that interacts simultaneously with the allosteric back pocket of these enzymes. We applied a combined computational strategy that started with the generation of two overlapping pharmacophore models of both kinases at 'inactive' conformation. Next, several virtual libraries of natural products, including the databases TCM (Traditional Chinese Medicine), UEFS (Universidade Estadual de Feira de Santana), NuBBE (Nuclei of Bioassays, Biosynthesis, and Ecophysiology of Natural Products) and AfroDb (African Medicinal Plants Database) were deconstructed using a non-extensive version of the approach RECAP (retrosynthetic combinatorial analysis procedure). These natural-product-derived fragments (NPDFs) were screened and merged into drug-sized compounds, which were filtered by Lipinski's Rule-of-five (Ro5) and docking. As a result, two pharmacophore models, namely Hypo1 and Hypo2, were developed with an accuracy of 0.94 and 0.84, respectively. Deconstruction of natural products produced a set of 16655 unique non-extensive NPDFs that were screened against both pharmacophore models. Finally, after merging, Ro5-filtering and docking, we obtained a set of 20 hit compounds predicted to be diverse, developable, synthesizable and potent. The computational strategy proved successful to find virtual candidates of kinase inhibitors and therefore contributes to the identification of innovative multi-target compounds with potential anticancer activity. Communicated by Ramaswamy H. Sarma.

Pushing the Ligand Efficiency Metrics: Relative Group Contribution (RGC) Model as a Helpful Strategy to Promote a Fragment "Rescue" Effect.

The ligand efficiency (LE) indexes have long been used as decision-making criteria in drug discovery and development. However, in the context of fragment-based drug design (FBDD), these metrics often exhibit a strong emphasis toward the selection of highly efficient "core" fragments for potential optimization, which are not usually considered as parts of a larger molecule with a size typical for a drug. In this study, we present a relative group contribution (RGC) model intended to predict the efficiency of a drug-sized compound in terms of its component fragments. This model could be useful not only in rapidly predicting all the possible combinations of promising fragments from an earlier hit discovery stage, but also in enabling a relatively low-LE fragment to become part of a drug-sized compound as long as it is "rescued" by other high-LE fragments.

Propuesta para la formación en Medicina Familiar y Comunitaria, desde la percepción, conceptualización y experiencia práctica de los enfoques de Salud Familiar / Proposal for training in Family and Community Medicine, from the perception, conceptualization and practical experience of Family Health approaches / Proposta de formação em Medicina Familiar e Comunitária, a partir da percepção, conceituação e experiência prática de abordagens de Saúde Familiar

Resumen La existencia de un Plan Decenal de Salud Pública para Colombia y la definición de una Política de Atención Integral en Salud concretaron un nuevo Modelo de Atención basado en la Atención Primaria de la Salud. Esto ubicó a la Salud Familiar y Comunitaria como núcleo fundamental y definió un rol al Médico y al Profesional Familiar y Comunitario, que dimensiona los procesos transdisciplinarios y la articulación de acciones individuales y colectivas, con esquemas pedagógicos holísticos transformadores. Este planteamiento generó un análisis y reflexión de la opinión de una muestra del 14,6% de los clasificados como Salubristas por el Observatorio Laboral del Ministerio de Educación quienes, con la respuesta a 13 preguntas enviadas por vía electrónica, libremente plantearon su percepción, conceptualización y experiencia práctica de los enfoques de Salud Familiar y Comunitaria. Con esta medición se definieron los contenidos básicos que se presentan en este documento con un nuevo enfoque transversal en el Pregrado y los Posgrados, de acuerdo con una propuesta pedagógica transformadora y con visión práctica, encontrándose aquí como destacable, la importante relación entre la educación y la salud integral; el concepto que en el 80% de las observaciones se expresó al denominar el poco compromiso de la comunidad y los profesionales de la salud con una "Cultura de la Salud Integralmente Concebida".

Abstract The existence of a Decennial Public Health Plan for Colombia and the definition of a Comprehensive Health Care Policy concretized a new Model of Care based on Primary Health Care. This placed Family and Community Health as a fundamental nucleus and defined a role for the Family and Community Physician and Practitioner, who dimension the transdisciplinary processes and the articulation of individual and collective actions, with transformational holistic pedagogical schemes. This approach generated an analysis and reflection of the opinion of a sample of 14.6% of those classified as Salubristas by the Labor Observatory of the Ministry of Education who, with the answer to 13 questions sent electronically, freely raised their perception, conceptualization and practical experience of Family and Community Health approaches. With this measurement the basic contents that are presented in this document with a new transversal approach in the Undergraduate and Postgraduates were defined, according to a pedagogical proposal transforming and with practical vision, being here like remarkable, the important relation between the education and integral health; the concept that in 80% of the observations was expressed when denominating the little commitment of the community and the professionals of the health with an "Culture of the Health Integrally Conceived".

Resumo A existência de um Plano de Saúde Pública de dez anos para a Colômbia ea definição de uma Política Integral de Saúde resultou em um novo Modelo de Cuidados Baseado em Atenção Primária à Saúde. Isso colocou a Familia e a Saúde Comunitária como um núcleo fundamental e definiu um papel para o Médico e o Profissional Familiar e Comunitário, que dimensiona os processos transdisciplinares e a articulação de ações individuais e coletivas, com esquemas pedagógicos transformadores holísticos. Esta abordagem gerou uma análise e reflexão da opinião de uma amostra de 14,6% das classificadas como Salubristas pelo Observatório do Trabalho do Ministério da Educação que, com a resposta a 13 questões enviadas eletronicamente, aumentou livremente sua percepção, conceituação e experiência prática de abordagens de saúde familiar e comunitária. Com esta medida, os conteúdos básicos apresentados neste documento foram definidos com um novo foco transversal em Estudos de Graduação e Pós-Graduação, de acordo com uma proposta pedagógica transformadora e com uma visão prática, sendo aqui a relação notável entre educação e saúde abrangente; o conceito de que em 80% das observações foi expressado chamando o pequeno compromisso da comunidade e os profissionais de saúde com uma "Cultura de Saúde Integralmente Concebida".