Inhibition pattern of sulfamide-related compounds in binding to carbonic anhydrase isoforms I, II, VII, XII and XIV

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Aceite de cáscara de citrus reticulata con potencial terapéuticos para el tratamiento de la aterosclerosis : estudios bioquímicos, moleculares y bioinformáticos

La aterosclerosis es una enfermedad cardiovascular (ECV) caracterizada por un engrosamiento de las paredes arteriales debido al depósito de lípidos principalmente el colesterol (Col) y a una respuesta inflamatoria crónica promovida por macrófagos y células espumosas. Las ECVs son la principal causa de muerte y discapacidad a nivel mundial siendo la hipercolesterolemia el factor que contribuye al 56% de los casos de cardiopatía coronaria. Los niveles de Col plasmático se regulan por mecanismos como la síntesis de novo del Col o vía del mevalonato (VM) principalmente activa en hepatocitos. En las primeras etapas de la VM (reacciones pre-escualeno) se generan isoprenoides no esteroideos como ubiquinona, dolicol y grupos prenilos.Fil: Castro, M.. Consejo Nacional de Investigaciones Científicas y TécnicasFil: Llanos, M.. Consejo Nacional de Investigaciones Científicas y TécnicasFil: Rodenak-kladniew, B.. Consejo Nacional de Investigaciones Científicas y TécnicasFil: Gavernet, L. Consejo Nacional de Investigaciones Científicas y TécnicasFil: García de Bravo, M. Consejo Nacional de Investigaciones Científicas y TécnicasFil: Crespo, R.. Consejo Nacional de Investigaciones Científicas y Técnica

Synthesis and biological evaluation of new antiseizure compounds derived from valproic acid

This article focuses on the design of new anticonvulsant compounds that combine the chemical structure of valproic acid with other interesting scaffolds with anticonvulsant or anti-inflammatory properties. These compounds protected against in vivo acute seizure models (mice). The results revealed the capacity of combining known scaffolds into a single structure to generate new active compounds with multitarget purposes.Facultad de Ciencias ExactasUniversidad de Buenos AiresLaboratorio de Investigación y Desarrollo de Bioactivo

Garbage in, garbage out: how reliable training data improved a virtual screening approach against SARS-CoV-2 MPro

Introduction: The identification of chemical compounds that interfere with SARS-CoV-2 replication continues to be a priority in several academic and pharmaceutical laboratories. Computational tools and approaches have the power to integrate, process and analyze multiple data in a short time. However, these initiatives may yield unrealistic results if the applied models are not inferred from reliable data and the resulting predictions are not confirmed by experimental evidence.Methods: We undertook a drug discovery campaign against the essential major protease (MPro) from SARS-CoV-2, which relied on an in silico search strategy –performed in a large and diverse chemolibrary– complemented by experimental validation. The computational method comprises a recently reported ligand-based approach developed upon refinement/learning cycles, and structure-based approximations. Search models were applied to both retrospective (in silico) and prospective (experimentally confirmed) screening.Results: The first generation of ligand-based models were fed by data, which to a great extent, had not been published in peer-reviewed articles. The first screening campaign performed with 188 compounds (46 in silico hits and 100 analogues, and 40 unrelated compounds: flavonols and pyrazoles) yielded three hits against MPro (IC50 ≤ 25 μM): two analogues of in silico hits (one glycoside and one benzo-thiazol) and one flavonol. A second generation of ligand-based models was developed based on this negative information and newly published peer-reviewed data for MPro inhibitors. This led to 43 new hit candidates belonging to different chemical families. From 45 compounds (28 in silico hits and 17 related analogues) tested in the second screening campaign, eight inhibited MPro with IC50 = 0.12–20 μM and five of them also impaired the proliferation of SARS-CoV-2 in Vero cells (EC50 7–45 μM).Discussion: Our study provides an example of a virtuous loop between computational and experimental approaches applied to target-focused drug discovery against a major and global pathogen, reaffirming the well-known “garbage in, garbage out” machine learning principle

Docking Applied to the Prediction of the Affinity of Compounds to P-Glycoprotein

P-Glycoprotein (P-gp) is involved in the transport of xenobiotic compounds and responsible for the decrease of the drug accumulation in multi drug-resistant cells. In this investigation we compare several docking algorithms in order to find the conditions that are able to discriminate P-gp binders and non-binders. We built a comprehensive data set of binders and non-binders based on a careful analysis of the experimental data available in the literature, trying to overcome the discrepancy noticeable in the experimental results. We found that Autodock Vina flexible docking is the best choice for the tested options. The results will be useful to filter virtual screening results in the rational design of new drugs that are not expected to be expelled by P-gp.Fil: Palestro, Pablo Hernán. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Cátedra de Química Medicinal; ArgentinaFil: Gavernet, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Cátedra de Química Medicinal; ArgentinaFil: Estiu, Guillermina L.. University of Notre Dame; Estados UnidosFil: Bruno Blanch, Luis Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Cátedra de Química Medicinal; Argentin

Sulfamide derivatives with selective carbonic anhydrase VII inhibitory action

A set of N,N0 -disubstituted sulfamides and sodium cyclamate have been tested for their inhibitory action against six isoforms of carbonic anhydrase (CA, EC 4.2.1.1) found in the brain, that is, CA I, CA II, CA VII, CA IX, CA XII and CA XIV, some of which are involved in epileptogenesis. The biological data showed interesting results for CA VII inhibition, the isozyme thought to be a novel antiepileptic target. Strong CA VII inhibitors, with Ki values in the low nanomolar–subnanomolar range were identified. Some of these derivatives showed selectivity for inhibition of CA VII versus the ubiquitous isoform CA II, for which the Ki values were in the micromolar range. Molecular modeling approaches were employed to understand the binding interactions between these compounds and the two CA isoforms, since the mechanism of action of such disubstituted sulfamides was not yet investigated by means of X-ray crystallographyFil: Villalba, Maria Luisa. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas; ArgentinaFil: Palestro, Pablo Hernán. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ceruso, Mariangela. Universita Degli Studi Di Firenze; ItaliaFil: Talevi, Alan. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gonzalez Funes, Jose L.. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas; ArgentinaFil: Bruno Blanch, Luis Enrique. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Supuran, Claudiu T.. Universita Degli Studi Di Firenze; ItaliaFil: Gavernet, Luciana. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

A structure-based approach towards the identification of novel antichagasic compounds: Trypanosoma cruzi carbonic anhydrase inhibitors

Trypanosoma cruzi carbonic anhydrase (TcCA) has recently emerged as an interesting target for the design of new compounds to treat Chagas disease. In this study we report the results of a structure-based virtual screening campaign to identify novel and selective TcCA inhibitors. The combination of properly validated computational methodologies such as comparative modelling, molecular dynamics and docking simulations allowed us to find high potency hits, with KI values in the nanomolar range. The compounds also showed trypanocidal effects against T. cruzi epimastigotes and trypomastigotes. All the candidates are selective for inhibiting TcCA over the human isoform CA II, which is encouraging in terms of possible therapeutic safety and efficacy

Synthesis of 2-Hydrazolyl-4-Thiazolidinones Based on Multicomponent Reactions and Biological Evaluation Against Trypanosoma Cruzi

A series of 18 novel 2-hydrazolyl-4-thiazolidinones-5-carboxylic acids, amides and 5,6-α,β-unsaturated esters were synthesized, and their in vitro activity on cruzipain and T. cruzi epimastigotes was determined. Some agents show activity at 37μm concentration in the enzyme assay. Computational tools and docking were used to correlate the biological response with the physicochemical parameters of the compounds and their cruzipain inhibitory effects. © 2011 John Wiley & Sons A/S