DSpace Coleção: PPGPN

AmIActive (AIA) : uma ferramenta web preditiva de larga escala baseada em QSAR para identificação de alvos e polifarmacologia

Fri, 20 Feb 2026 00:00:00 GMT

Título: AmIActive (AIA) : uma ferramenta web preditiva de larga escala baseada em QSAR para identificação de alvos e polifarmacologia Autor(es): Melo, Luis Felipe de Morais Orientador: Scotti, Marcus Tullius Abstract: Computer-aided drug design (CADD) has become a cornerstone of modern drug discovery, with approaches such as ligand-based methods (e.g., QSAR-Quantitative Structure Activity Relationships modeling and pharmacophore analysis) and structure- based methods (e.g., molecular docking and molecular dynamics) driving innovation. Ligand-based strategies remain essential, particularly in light of the growing availability of large-scale biological activity data. As a result, over the years, several QSAR-based predictive platforms available on the internet have shaped the field, including PASS, PLATO, and SwissTargetPrediction, among others. Although this ecosystem has continuously expanded since its inception, the dynamic nature of computational methodologies and the wide diversity of possible approaches have consistently left room for the development of new tools and the optimization of existing ones. Accordingly, the aim of this study was to develop the first Brazilian tool of this type. In this context, we present AmIActive (AIA), a large-scale QSAR-based predictive web tool designed to facilitate target fishing studies and polypharmacology assessment for both molecular and non-molecular targets. Chapter 1 presents a review of the fundamental methodologies and theoretical concepts required for the technical and conceptual understanding of a QSAR system of this type, while Chapter 2 describes the development of the AIA system itself. The AIA system integrates 3,239 statistically validated QSAR models covering 2,277 distinct targets, including single proteins, protein complexes, protein families, cell lines, organisms, and tissues. Pharmacological data were extracted from ChEMBL30 and subjected to rigorous cleaning and standardization procedures, with the exclusion of unsuitable datasets and conversion of activity values to negative logarithmic scales (pIC50, pAC50). Classification thresholds separating active and inactive compounds were defined using a binary search algorithm to achieve balanced classes. ECFP4 molecular fingerprints (1024 bits) were used as input features, and models were built using the Random Forest algorithm, with Bayesian hyperparameter optimization and nested cross-validation. Only models with p-values < 0.05 and MCC ≥ 0.5 were retained, yielding robust average performance (accuracy ≈ 0.82, F1-score ≈ 0.82, MCC ≈ 0.65). Applicability domains were defined using a normalized Euclidean distance metric, in accordance with OECD (Organisation for Economic Co-operation and Development) QSAR guidelines. The system is freely available at https://amiactive.ccen.ufpb.br/ through an intuitive graphical interface based on ChemAxon’s MarvinJS, allowing users to draw chemical structures or input SMILES strings and export prediction results in CSV format, including predicted activity probabilities, classification thresholds, applicability domain reliability, and complete model validation metrics. Editor: Universidade Federal da Paraíba Tipo: Dissertação

Estudo integrado do potencial ansiolítico-símile e neuroprotetor do derivado tiofênico 6CN07 : abordagens in silico, in vivo e in vitro

Wed, 25 Feb 2026 00:00:00 GMT

Título: Estudo integrado do potencial ansiolítico-símile e neuroprotetor do derivado tiofênico 6CN07 : abordagens in silico, in vivo e in vitro Autor(es): Barbosa, Nayana Maria Medeiros Vilar Orientador: Felipe, Cícero Francisco Bezerra Abstract: Anxiety disorders represent a significant public health challenge, and despite the diversity of anxiolytic drugs available, treatment remains limited by unsatisfactory clinical responses and adverse effects that compromise patient adherence. These factors highlight the urgent need to investigate new compounds with more effective and safer pharmacological profiles. In this context, the present study aimed to investigate the anxiolytic-like potential of the thiophene derivative 6CN07 and its possible mechanism of action through in silico, in vivo, and in vitro approaches. In silico analyses indicated that 6CN07 presented physicochemical and pharmacokinetic properties compatible with central nervous system-acting drugs, in addition to favorable interactions with key targets involved in the neurobiology of anxiety, namely 5 -HT1A, 5-HT2A, and GABA receptors. Regarding in vivo methodologies, 6CN07 promoted anxiolytic-like effects in mice subjected to the Elevated Plus Maze (EPM) and Light-Dark Box (LDB) tests, without inducing impairment in locomotor activity or motor coordination. Pharmacological antagonism studies indicated the possible involvement of GABAA and 5-HT2A receptors in the compound's effect. Additionally, 6CN07 exhibited an anxiolytic-like effect in the pentylenetetrazol (PTZ)-induced anxiety model and attenuated the oxidative stress associated with this model. Finally, in vitro analyses performed on astrocyte cultures in the presence of glutamate showed that 6CN07 preserved cell viability against glutamatergic excitotoxicity, suggesting a potential neuroprotective effect. Taken together, these results suggest that compound 6CN07 possesses a pharmacokinetic and physicochemical profile compatible with anxiolytic drugs, whose mechanism of action appears to involve GABAergic and serotonergic neurotransmission, attenuation of oxidative stress, and neuroprotection against glutamatergic excitotoxicity. However, further studies at the molecular level are necessary for a better understanding of this thiophene derivative's effects. Editor: Universidade Federal da Paraíba Tipo: Dissertação

Do conhecimento à aplicação: triagem virtual e aplicação experimental de compostos fenólicos e de terpenos da família fabaceae para estratégias multialvo contra doenças tropicais negligenciadas e doenças virais emergentes

Fri, 29 Aug 2025 00:00:00 GMT

Título: Do conhecimento à aplicação: triagem virtual e aplicação experimental de compostos fenólicos e de terpenos da família fabaceae para estratégias multialvo contra doenças tropicais negligenciadas e doenças virais emergentes Autor(es): Sousa, Natalia Ferreira de Orientador: Scotti, Marcus Tullius Abstract: Neglected diseases and emerging viral infections, such as that caused by SARS-CoV-2 the etiological agent of the COVID-19 pandemic (March 11, 2020, to May 5, 2023), pose a serious challenge to global public health, primarily affecting low-income populations and regions with poor infrastructure. The limited efficacy of existing therapies, often associated with high toxicity and the development of resistance to conventional drugs, underscores the need for new strategies in drug discovery. In this context, secondary metabolites from the Fabaceae family stand out as promising sources of bioactive molecules. This family is considered one of the most representative in the plant kingdom, being particularly rich in phenolic compounds and terpenoids, classes widely recognized for their broad spectrum of biological activities. Among the phenolic compounds, chalcones deserve special attention due to their structural diversity and pharmacological potential, including antiparasitic and antiviral properties. Similarly, terpenes especially those belonging to the triterpenoid class are abundant in Fabaceae species and have demonstrated significant effects against different pathogens. Based on this scenario, this Ph.D. thesis aimed to identify and propose new drug candidates through integrated strategies involving Cheminformatics, Medicinal Chemistry, virtual screening, and experimental validation. Initially, reviews were conducted on recent advances in rational drug design for neglected diseases, with an emphasis on multitarget compounds and key enzymes of parasite energy metabolism, such as succinate dehydrogenase. In the computational phase, in silico methodologies were applied, including pharmacophore modeling and QSAR, targeting phenolic and terpenoid derivatives from the Fabaceae family. Virtual screening was complemented by molecular docking and structure-activity relationship (SAR) analyses, prioritizing compounds with higher predicted biological activity. Among the main findings, chalcones with potent antimalarial action (Plasmodium falciparum, IC₅₀ < 10 μM, SI > 12) and triterpenoids with anti-SARS-CoV-2 activity were identified, particularly those from the Lupane series, with emphasis on betulinic acid, whose activity was confirmed in phenotypic assays, showing viral inhibition above 50% and cell viability above 70%. These results highlight the potential of integrating computational tools and experimental approaches to accelerate the discovery of new therapeutic candidates, contributing to the development of innovative strategies to combat tropical diseases and emerging viral infections. Editor: Universidade Federal da Paraíba Tipo: Tese

Avaliação in vitro da atividade anti-Leishmania de fitocanabinoides de Cannabis sativa

Wed, 25 Feb 2026 00:00:00 GMT

Título: Avaliação in vitro da atividade anti-Leishmania de fitocanabinoides de Cannabis sativa Autor(es): Santos, Fernando Cézar Comberlang Queiroz Davis dos Orientador: Lima, Tatjana Keesen de Souza Abstract: Leishmaniasis is considered a neglected tropical disease affecting socially vulnerable populations, with an estimated 1.5 to 2 million new cases annually. Leishmania spp. is an obligate intracellular parasite that exhibits two evolutionary stages: the extracellular promastigote form and the intracellular amastigote form. Regarding the clinical aspects of leishmaniasis, the disease presents in cutaneous, mucocutaneous, and visceral forms, the latter being the most severe and lethal. Despite its epidemiological relevance, pharmacotherapy remains largely unchanged, with drugs exhibiting high toxicity, administration difficulties, and the development of parasite resistance. Given the potential of Cannabis sativa as a source of bioactive compounds with pharmacological properties used in the treatment of epilepsy and Alzheimer's disease, other antibacterial, antifungal, antiparasitic, and anti-inflammatory activities have already been studied. Therefore, this study aims to evaluate the in vitro biological activity of different extracts rich in phytocannabinoids (CBG, CBD, THC, and THCV) against L. infantum forms, as well as their effect on the production of reactive oxygen species (ROS) by monocytes during infection. To this end, cultures of promastigotes, amastigotes, erythrocytes, and peripheral blood mononuclear cells (PBMCs), infected and uninfected, were treated with the phytocannabinoid extracts. The activity of the extracts in killing the different parasite forms, cytotoxicity on human cells, and ROS production were evaluated. The results showed that the phytocannabinoids exhibit anti-promastigote and anti-amastigote activities and moderate cytotoxicity against PBMCs, without evidence of erythrocyte hemolysis. Furthermore, CBD, CBG, and THCV reduced ROS production in infected monocytes. These results suggest that Cannabis sativa extracts may help control the parasite and modulate the inflammatory response. However, further studies are needed to elucidate the mechanisms involved and to further evaluate the safety profile, considering the potential use of phytocannabinoids as a therapeutic alternative in leishmaniasis. Editor: Universidade Federal da Paraíba Tipo: Dissertação