Pharmacokinetics Profiler (PhaKinPro): Model Development, Validation, and Implementation as a Web Tool for Triaging Compounds with Undesired Pharmacokinetics Profiles.

Computational models that predict pharmacokinetic properties are critical to deprioritize drug candidates that emerge as hits in high-throughput screening campaigns. We collected, curated, and integrated a database of compounds tested in 12 major end points comprising over 10,000 unique molecules. We then employed these data to build and validate binary quantitative structure-activity relationship (QSAR) models. All trained models achieved a correct classification rate above 0.60 and a positive predictive value above 0.50. To illustrate their utility in drug discovery, we used these models to predict the pharmacokinetic properties for drugs in the NCATS Inxight Drugs database. In addition, we employed the developed models to predict the pharmacokinetic properties of all compounds in the DrugBank. All models described in this paper have been integrated and made publicly available via the PhaKinPro Web-portal that can be accessed at https://phakinpro.mml.unc.edu/.

Ligand-based virtual screening, molecular dynamics, and biological evaluation of repurposed drugs as inhibitors of Trypanosoma cruzi proteasome.

Chagas disease is a well-known Neglected Tropical Disease, mostly endemic in continental Latin America, but that has spread to North America and Europe. Unfortunately, current treatments against such disease are ineffective and produce known and undesirable side effects. To find novel effective drug candidates to treat Chagas disease, we uniquely explore the Trypanosoma cruzi proteasome as a recent biological target and, also, apply drug repurposing through different computational methodologies. For this, we initially applied protein homology modeling to build a robust model of proteasome ß4/ß5 subunits, since there is no crystallographic structure of this target. Then, we used it on a drug repurposing via a virtual screening campaign starting with more than 8,000 drugs and including the methodologies: ligand-based similarity, toxicity predictions, and molecular docking. Three drugs were selected concerning their favorable interactions at the protein binding site and subsequently submitted to molecular dynamics simulations, which allowed us to elucidate their behavior and compare such theoretical results with experimental ones, obtained in biological assays also described in this paper.Communicated by Ramaswamy H. Sarma.

Chromatographic profile, in silico and in vivo study of the pharmacokinetic and toxicological properties of major constituent present in kefir, the kefiran.

Kefiran is a polysaccharide present in kefir grains that have been widely explored due to its potential health benefits. The objective of this work was to characterize and quantify the components present in the ethanolic extract of milk kefir grains; to study its pharmacokinetic and toxicological properties in silico and evaluate the acute toxicity of the kefiran in zebrafish. The prediction of pharmacokinetic properties was performed by QikProp software. In silico toxicity assessment was performed using the DEREK (deductive estimate of risk from existing knowledge) software. In the chromatographic, kefiran was identified as the major component. Results showed that the kefiran had low human oral absorption and intestinal absorption its due poor solubility profile; low logP value, indicating its lipophilicity and the low MDCK and Caco-2 cells permability, and unable to cross the blood-brain barrier. Kefiran did not present any structural warning for in silico toxicity. In zebrafish, the dose of 2,000 mg/kg of kefiran produced nonsignificant alterations in the analyzed organs. It can be said then that kefiran has an acceptable degree of safety for use in the development of drugs or functional foods. Further research such as in vivo testing to confirm its pharmacological potential is currently underway.

Potential colchicine binding site inhibitors unraveled by virtual screening, molecular dynamics and MM/PBSA.

Microtubules have been widely studied in recent decades as an important pharmacological target for the treatment of cancer especially due to its key role in the mitosis process. Among the constituents of the microtubules, αß-tubulin dimers stand out in view of their four distinct interaction sites, including the so-called colchicine binding site (CBS) - a promising target for the development of new tubulin modulators. When compared to other tubulin sites, targeting the CBS is advantageous because this site is able to host ligands with lower molecular volume and lipophilicity, thus reducing the chances of entailing the phenomenon of multiple drug resistance (MDR) - one of the main reasons of failure in chemotherapy. However, colchicine, the first ligand ever discovered with affinity towards the CBS, despite modulating the action of microtubules, has shown toxicity in clinical studies. Therefore, in order to expand the known chemical space of scaffolds capable of interacting with CBS and to design non-toxic colchicine binding site inhibitors, we conducted a robust virtual screening pipeline. This has been rigorously validated and consisted of ligand- and structure-based methodologies, which allowed us to select four promising CBS inhibitors called tubLCQF1-4. These four compounds were also evaluated with long trajectories molecular dynamics simulations and respective results were used for the theoretical determination of the free energy released in the formation of the complexes, using the Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) methodology.

Synthesis, antitumor activity and in silico analyses of amino acid derivatives of artepillin C, drupanin and baccharin from green propolis.

Breast cancer has the highest incidence and mortality in females, while prostate cancer has the second-highest incidence in males. Studies have shown that compounds from Brazilian green propolis have antitumor activities and can selectively inhibit the AKR1C3 enzyme, overexpressed in hormone-dependent prostate and breast tumors. Thus, in an attempt to develop new cytotoxic inhibitors against these cancers, three prenylated compounds, artepillin C, drupanin and baccharin, were isolated from green propolis to synthesize new derivatives via coupling reactions with different amino acids. All obtained derivatives were submitted to antiproliferative assays against four cancer cells (MCF-7, MDA MB-231, PC-3, and DU145) and two normal cell lines (MCF-10A and PNT-2) to evaluate their cytotoxicity. In general, the best activity was observed for compound6e, derived from drupanin, which exhibited half-maximal inhibitory concentration (IC50) of 9.6 ± 3 µM and selectivity index (SI) of 5.5 against MCF-7 cells.In silicostudies demonstrated that these derivatives present coherent docking interactions and binding modes against AKR1C3, which might represent a possible mechanism of inhibition in MCF-7 cells.

Identification of known drugs as potential SARS-CoV-2 Mpro inhibitors using ligand- and structure-based virtual screening.

Background: The new coronavirus pandemic has had a significant impact worldwide, and therapeutic treatment for this viral infection is being strongly pursued. Efforts have been undertaken by medicinal chemists to discover molecules or known drugs that may be effective in COVID-19 treatment - in particular, targeting the main protease (Mpro) of the virus. Materials & methods: We have employed an innovative strategy - application of ligand- and structure-based virtual screening - using a special compilation of an approved and diverse set of SARS-CoV-2 crystallographic complexes that was recently published. Results and conclusion: We identified seven drugs with different original indications that might act as potential Mpro inhibitors and may be preferable to other drugs that have been repurposed. These drugs will be experimentally tested to confirm their potential Mpro inhibition and thus their effectiveness against COVID-19.

Molecular Docking, Physicochemical Properties, Pharmacokinetics and Toxicity of Flavonoids Present in Euterpe oleracea Martius.

BACKGROUND: Euterpe oleracea Martius, popularly known as açaí, is a fruit rich in α- tocopherols, fibers, lipids, mineral ions, and polyphenols. It is believed that the high content of polyphenols, especially flavonoids, provides several health-promoting effects to the açaí fruit, including anti-inflammatory, immunomodulatory, antinociceptive and antioxidant properties. Most of the flavonoids are antioxidant molecules of plant origin that act as a trap for free radicals, reacting and neutralizing them, thus offering perspectives in preventing oxidative damage. OBJECTIVE: In this study, we aim to perform an in silico evaluation of flavonoids present in the pulp and the oil of Euterpe oleracea Martius, evaluating their potential to serve as antioxidant agents. METHODS: Firstly, we selected 16 flavonoids present in Euterpe oleracea Martius pulp and oil, and then their physicochemical properties were analyzed concerning the Lipinski's Rule of Five. Moreover, we evaluated their pharmacokinetic properties using the QikProp module of the Schrödinger software as well as their toxicity profile, using the DEREK software. Docking simulations, using the GOLD 4.1 software, as well as pharmacophoric hypotheses calculation of molecules were also performed. RESULTS: Flavonoids present in the açaí pulp including catechin, epicatechin, luteolin, chrisoeriol, taxifolin, apigenin, dihydrokaempferol, isovitexin, and vitexin presented good oral bioavailability. Regarding the pharmacokinetic properties, the compounds catechin, epicatechin, isovitexin, luteolin, chrisoeriol, taxifolin, and isorhamnetin rutinoside presented the best results, besides high human oral absorption. Regarding the prediction of toxicological properties, compounds isorhamnetin rutinoside and rutin presented mutagenicity for hydroxynaphthalene or derivate, and regarding the docking simulations, all the compounds investigated in this study presented key interactions with the corresponding targets. CONCLUSION: The flavonoids catechin, chrysoeriol, and taxifolin presented the best results according to the evaluation conducted in this study. These computational results can be used as a theoretical basis for future studies concerning the development of drug candidates, as well as to enlighten biological tests in vitro and in vivo, which can contribute to the treatment of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease.

Identification of novel αß-tubulin modulators with antiproliferative activity directed to cancer therapy using ligand and structure-based virtual screening.

Among several strategies related to cancer therapy targeting the modulation of αß-tubulin has shown encouraging findings, more specifically when this is achieved by inhibitors located at the colchicine binding site. In this work, we aim to fish new αß-tubulin modulators through a diverse and rational VS study, and thus, exhibiting the development of two VS pipelines. This allowed us to identify two compounds 5 and 9 that showed IC50 values of 19.69 and 21.97 µM, respectively, towards possible modulation of αß-tubulin, such as assessed by in vitro assays in C6 glioma and HEPG2 cell lines. We also evaluated possible mechanisms of action of obtained hits towards the colchicine binding site of αß-tubulin by using docking approaches. In addition, assessment of the stability of the active (5 and 9) and inactive compounds (3 and 13) within the colchicine binding site was carried out by molecular dynamics (MD) simulations, highlighting the solvent effect and revealing the compound 5 as the most stable in the complex. At last, deep analysis of these results provided some valuable insights on the importance of using mixed ligand- and structure-based strategies in VS campaigns, in order to achieve higher chemical diversity and biological effect as well.

Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review.

Among neurodegenerative disorders, Alzheimer's disease (AD) is the most common type of dementia, and there is an urgent need to discover new and efficacious forms of treatment for it. Pathological patterns of AD include cholinergic dysfunction, increased ß-amyloid (Aß) peptide concentration, the appearance of neurofibrillary tangles, among others, all of which are strongly associated with specific biological targets. Interactions observed between these targets and potential drug candidates in AD most often occur by competitive mechanisms driven by orthosteric ligands that sometimes result in the production of side effects. In this context, the allosteric mechanism represents a key strategy; this can be regarded as the selective modulation of such targets by allosteric modulators in an advantageous manner, as this may decrease the likelihood of side effects. The purpose of this review is to present an overview of compounds that act as allosteric modulators of the main biological targets related to AD.

Saúde da população LGBT+ no contexto da atenção primária em saúde: relato de oficina realizada no internato integrado de Medicina de Família e Comunidade/Saúde Mental em uma universidade pública / LGBT+ Health on Primary Care: the experience report of a workshop during the medical internship on Family Medicine and Mental Health in a public university / Salud de la población LGBT + en el contexto de la atención primaria en salud: relato de taller realizado en el internado integrado de Medicina de Familia y Comunidad/Salud Mental en una universidad pública

Introdução: A saúde da população LGBT+ apresenta particularidades e vulnerabilidades que requerem atenção diferenciada. Sensibilizar e qualificar profissionais de saúde para as necessidades dessa população é fundamental para garanti-la o direito à saúde. Os currículos das graduações em saúde, que em geral não incorporam tais questões, têm sido interrogados pelo alunado com denúncias de LGBTfobia no curso médico e reivindicação de capacitação prática. Nesse contexto, o Internato Integrado de Medicina de Família e Comunidade e Saúde Mental da Faculdade de Medicina da Universidade Federal do Rio de Janeiro organizou oficina sobre Saúde da População LGBT, apresentada neste artigo. Métodos: Realizada em maio de 2018, teve como público alvo internos em estágio curricular na Atenção Primária em Saúde (APS), no município do Rio de Janeiro. Sensibilizar para o tema e apresentar ferramentas úteis para o cuidado na APS, e em outros cenários, foram os objetivos. Graduandos de medicina autodeclarados LGBT+ foram convidados a assumir a condução da atividade, preparada sob orientação de professoras do internato. O protagonismo dado a esses alunos permitiu articular à expertise científica, promovida nos estudos regulares sobre o tema, a expertise experiencial. A oficina ocorreu em 4 tempos: i) sensibilização; ii) discussão de casos; iii) informação e exposição de orientações para boas práticas em saúde; iv) dúvidas e avaliação. A duração total foi de 4 horas, com metodologias ativas e participativas. Resultados: Os objetivos foram alcançados e a atividade bem avaliada em sua organização e execução. Avaliação narrativa foi realizada com alunos e professores organizadores. Os internos participantes responderam questionário online com perguntas abertas e fechadas e também avaliaram positivamente a atividade nos quesitos metodologia e conteúdo. Conclusão/Desdobramentos: A oficina foi incluída nas atividades regulares do internato. Estão em construção, com vistas a difundir esses conhecimentos a outros estudantes do curso médico e a profissionais da rede de saúde municipal, disciplina eletiva e projeto de extensão. A inclusão longitudinal do tema no currículo permanece como desafio.

Introduction: The LGBT+ healthcare is marked with particularities and vulnerabilities that require differenced attention. Sensitizing and qualifying healthcare professionals to these population's needs is fundamental to guarantee the right to health. The curriculum from health degrees, that usually does not address this issue, have been questioned by students along with LGBTphobia reports among the medical education and revindication for practical capacitation. In this context, the Integrated Family & Community Medicine (MFC) and Mental Health Internship at Faculty of Medicine of the Federal University of Rio de Janeiro, prepared a workshop on LGBT Health, presented in this article. Methods: A workshop took place in May of 2018, having a target audience of interns of MFC. It aimed to sensitize medical students regarding the referred theme and to give practical tools to be used in primary medicine and other healthcare environments. Medical undergrads who identify themselves as LGBT+ were invited to conduct the activity under the orientation of tutors from the internship. Given that those medical students were protagonists in this activity, it was possible to articulate the scientific knowledge, accomplished with regular studies on the theme, and the experiential expertise. The workshop was divided in four acts: i) sensitization; ii) case discussion; iii) information and orientations on good practice; iv) questions and feedback. The workshop lasted 4 hours, using active and participatory learning methods. Results: The objectives were achieved with a highly good evaluation as to the workshop's organization and performance. The students and professors that coordinated the activity prepared a narrative evaluation. The workshop's subjects, the MFC interns, took later an online feedback questionnaire, in which they positively evaluated the methods and acquired knowledge. Conclusion/Future works: The workshop, firstly implemented as an experimental activity, is now part of the regular medical internship curriculum. An optative course and an extension project are being planned, aiming to reach other medical students and public healthcare providers. Including the subject in the medical curriculum as a longitudinal discussion remains a challenge.

Introducción: La atención médica LGBT + está señalada con particularidades y vulnerabilidades que requieren una atención diferenciada. Sensibilizar y calificar a los profesionales de la salud de las necesidades de esta población es fundamental para garantizar su derecho a la salud. El plan de estudios de las carreras de salud, que en general no abordan este tema, ha sido cuestionado por los estudiantes junto con los informes de LGBTphobia entre la educación médica y la reivindicación de la capacitación práctica. En este contexto, la Pasantía Integrada de la Medicina de la Família y la Comunidad y Salud Mental de la graduación en medicina de la Universidad Federal de Rio de Janeiro elaboró un taller sobre salud LGBT+, presentado en este artículo. Métodos: Realizado en mayo de 2018 con los internos en pasantía curricular en la APS como el público-objetivo. Los objetivos eran sensibilizar a los estudiantes de medicina sobre el tema presentado y ofrecer herramientas prácticas para que las utilicen en la medicina primaria y en otros entornos de atención médica. Se invitó a los estudiantes de medicina que se identifican a sí mismos como LGBT+, para realizar la actividad bajo la orientación de tutores de la pasantía. Como los estudiantes de medicina fueron los protagonistas de esta actividad, fue posible articular el conocimiento científico, realizado con estudios regulares sobre el tema y la vivencia experiencial. El taller se dividió en cuatro partes: i) sensibilización; ii) discusión del caso; iii) información y orientaciones sobre buenas prácticas; iv) preguntas y comentarios. El taller tuvo una duración de cuatro horas, utilizando métodos de aprendizaje activo y participativo. Resultados: Los objetivos se lograron con una evaluación muy buena de la organización y el desempeño del taller. Los estudiantes y profesores que coordinaron la actividad realizaron una evaluación narrativa. Los pasantes presentes contestaron a un cuestionario en línea con preguntas objetivas y abiertas y evaluaron positivamente la actividad tanto por su metodología como por el contenido. Conclusión/Desarrollo: El taller, implementado como una actividad experimental, ahora forma parte del plan de estudios de prácticas médicas regulares. Se está planificando un curso optativo y un proyecto de extensión, con el objetivo de llevar eses conocimientos a otros estudiantes de medicina y proveedores de la salud pública. Incluir el tema en los planes de estudios médicos como una discusión longitudinal sigue siendo un desafío.