Small molecule stabilization of non-native protein-protein interactions of SARS-CoV-2 N protein as a mechanism of action against COVID-19

The outbreak of COVID-19, the disease caused by SARS-CoV-2, continues to affect millions of people around the world. The absence of a globally distributed effective treatment makes the exploration of new mechanisms of action a key step to address this situation. Stabilization of non-native Protein-Protein Interactions (PPIs) of the nucleocapsid protein of MERS-CoV has been reported as a valid strategy to inhibit viral replication. In this study, the applicability of this unexplored mechanism of action against SARS-CoV-2 is analyzed. During our research, we were able to find three inducible interfaces of SARS-CoV-2 N protein NTD, compare them to the previously reported MERS-CoV stabilized dimers, and identify those residues that are responsible for their formation. A drug discovery protocol implemented consisting of docking, molecular dynamics and MM-GBSA enabled us to find several compounds that might be able to exploit this mechanism of action. In addition, a common catechin skeleton was found among many of these molecules, which might be useful for further drug design. We consider that our findings could motivate future research in the fields of drug discovery and design towards the exploitation of this previously unexplored mechanism of action against COVID-19.Fil: Fernández, Julián Francisco. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; ArgentinaFil: Lavecchia, Martín José. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Química Inorgánica "Dr. Pedro J. Aymonino". Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Química Inorgánica "Dr. Pedro J. Aymonino"; Argentin

Estudio teórico de una familia de N-glicosilsulfonamidas con actividad farmacológica

En el presente trabajo se estudia, desde el punto de vista computacional y utilizando métodos semiempíricos y herramientas de la teoría del funcional de la densidad, propiedades de una familia de N-glicosilsulfonamidas con actividad farmacológica con el fin de profundizar la comprensión de distintos parámetros estructurales y espectroscópicos de las mismas. En primera instancia, una vez determinada la validez de la metodología (Parte I, pag. 13), se calcularon propiedades no accesibles experimentalmente pero de gran utilidad para el entendimiento estructural y espectroscópico de estas moléculas(Parte II, pag. 89). Asimismo, se inició un estudio preliminar para intentar comprender la actividad presentada por estos compuestos mediante la utilización de descriptores moleculares y la técnica de acoplamiento molecular con un método desarrollado en este trabajo (Parte III, pag. 151).Facultad de Ciencias Exacta

Small molecule stabilization of non-native protein-protein interactions of SARS-CoV-2 N protein as a mechanism of action against COVID-19

The outbreak of COVID-19, the disease caused by SARS-CoV-2, continues to affect millions of people around the world. The absence of a globally distributed effective treatment makes the exploration of new mechanisms of action a key step to address this situation. Stabilization of non-native Protein-Protein Interactions (PPIs) of the nucleocapsid protein of MERS-CoV has been reported as a valid strategy to inhibit viral replication. In this study, the applicability of this unexplored mechanism of action against SARS-CoV-2 is analyzed. During our research, we were able to find three inducible interfaces of SARS-CoV-2 N protein NTD, compare them to the previously reported MERS-CoV stabilized dimers, and identify those residues that are responsible for their formation. A drug discovery protocol implemented consisting of docking, molecular dynamics and MM-GBSA enabled us to find several compounds that might be able to exploit this mechanism of action. In addition, a common catechin skeleton was found among many of these molecules, which might be useful for further drug design. We consider that our findings could motivate future research in the fields of drug discovery and design towards the exploitation of this previously unexplored mechanism of action against COVID-19.Centro de Química Inorgánic

On the discovery of a potential survivin inhibitor combining computational tools and cytotoxicity studies

Survivin protein is a metalloprotein member of the inhibitors of apoptosis proteins family, involved in the regulation of programmed cell death. Due to the recent development of antitumor therapies having survivin as molecular target, several strategies to interfere with the expression or function of survivin have emerged. This work describes the discovery of a new potential inhibitor of survivin function using a computer-aided drug design approach. Structure-based virtual screening and molecular dynamic simulations were carried out to select two compounds as possible inhibitors. According to the binding energy, possible ligand localization is in a cavity, close to dimerization interface. Next, cell-based assays were performed on three cell lines: two with tumor phenotype and over-expression of survivin, and another with normal phenotype and low expression of survivin. One of the selected compounds shows a selectively antitumor effect on panel cell lines suggesting that the compound effect could be correlated with the survivin expression.Fil: Quispe Castillo, Patricia Araceli. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Química Inorgánica "Dr. Pedro J. Aymonino". Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Química Inorgánica "Dr. Pedro J. Aymonino"; ArgentinaFil: Lavecchia, Martín José. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Química Inorgánica "Dr. Pedro J. Aymonino". Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Química Inorgánica "Dr. Pedro J. Aymonino"; ArgentinaFil: Leon, Ignacio Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Química Inorgánica "Dr. Pedro J. Aymonino". Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Química Inorgánica "Dr. Pedro J. Aymonino"; Argentin

Computational chemical analysis of unconjugated bilirubin anions and insights into pKa values clarification

The pKa, the negative logarithm of the acid dissociation equilibrium constant, of the carboxylic acid groups of unconjugated bilirubin in water is a discussed issue because there are quite different experimental values reported. Using quantum mechanical calculations we have studied the conformational behavior of unconjugated bilirubin species (in gas phase and in solution modeled implicitly and explicitly) to provide evidence that may clarify pKa values because of its pathophysiological relevance. Our results show that rotation of carboxylate group, which is not restricted, settles it in a suitable place to establish stronger interactions that stabilizes the monoanion and the dianion to be properly solvated, demonstrating that the rationalization used to justify the high pKa values of unconjugated bilirubin is inappropriate. Furthermore, low unconjugated bilirubin (UCB) pKa values were estimated from a linear regression analysis.Centro de Química Inorgánic

Vanillin enones as selective inhibitors of the cancer associated carbonic anhydrase isoforms IX and XII: The out of the active site pocket for the design of selective inhibitors?

New C-glycosides and a,b-unsaturated ketones incorporating the 4-hydroxy-3-methoxyphenyl (vanillin) moiety as inhibitors of carbonic anhydrase (CA, EC 4.2.1.1) isoforms have been investigated. The inhibition profile of these compounds is presented against four human CA (hCA) isozymes, comprising hCAs I and II (cytosolic, ubiquitous enzymes) and hCAs IX and XII (tumour associated isozymes). Docking analysis of the inhibitors within the active sites of these enzymes has been performed and is discussed, showing that the observed selectivity could be explained in terms of an alternative pocket out of the CA active site where some of these compounds may bind. Several derivatives were identified as selective inhibitors of the tumour-associated hCA IX and XII. Their discovery might be a step in the strategy for finding an effective non-sulfonamide CA inhibitor useful in therapy/diagnosis of hypoxic tumours or other pathologies in which CA isoforms are involved.Fil: Riafrecha, Leonardo Ezequiel. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Química. Laboratorio de Estudio de Compuestos Orgánicos; Argentina. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Le Pors, Macarena Soledad. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Química. Laboratorio de Estudio de Compuestos Orgánicos; Argentina. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Lavecchia, Martín José. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Química Inorgánica "Dr. Pedro J. Aymonino". Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Química Inorgánica "Dr. Pedro J. Aymonino"; ArgentinaFil: Bua, Silvia. Università degli Studi di Firenze; ItaliaFil: Supuran, Claudiu T.. Università degli Studi di Firenze; ItaliaFil: Colinas, Pedro Alfonso. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Química. Laboratorio de Estudio de Compuestos Orgánicos; Argentina. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentin

Use of Informatic Resources as a Complement in the Teaching of Chemistry

La amplia divulgación de las computadoras personales facilita el acceso de amplios sectores de la población a tener esta tecnología al alcance de la mano. En los últimos años, con la creación y extensión masiva de la red de redes, o Internet, ha permitido una extensa difusión del conocimiento y el consecuente desarrollo de aplicaciones informáticas de creación individual o grupal. Muchas de estas aplicaciones son gratuitas, al menos para instituciones educativas, y otro tanto de código abierto, lo que invita a entender su funcionamiento y aventurarse a producir modificaciones. Como la Química es una ciencia que se puede entender a dos niveles, el macroscópico y el molecular, su enseñanza debe apuntar a ambos para lograr una comprensión general. El nivel molecular frecuentemente causa mayores problemas a los estudiantes, razón por la cuál debe ser fortalecido. En este trabajo pretendemos acercar las posibilidades que ofrecen los recursos informáticos como apoyo a la enseñanza de la Química, haciendo hincapié en el nivel molecular. Se esboza una clasificación general de las aplicaciones informáticas que sirven de apoyo a la enseñanza de la Química, según su función, en Visualizadores, Editores, Simulación, Cálculos de Química Computacional, Recursos Específicos Educativos y Programación. También se mencionan algunos ejemplos gratuitos de cada tipo, sin pretender que esto impida una búsqueda personalizada de otras aplicaciones disponibles.The increasingly widespread use of personal computers provides access to broad segments of the population to have technology at their fingertips. In recent years, the extensive use of the Internet has allowed an important dissemination of knowledge and the consequent development of new, useful software. Many of those applications are free, at least for educational institutions, and likewise open source, a feature that invites to understand how programs work and, eventually, to introduce improvements which become available to the rest of the community. As Chemistry is a science that can be understood both at a macroscopic and at a molecular level, an efficient teaching should aim to achieve a general understanding at the two levels. The molecular level of understanding often causes major problems for students and should be strengthened. In this work it is tried to bring the potential of computing resources to support the teaching of Chemistry, with emphasis on the molecular level of understanding. A general classification of computer applications that can be used to improve Chemistry teaching is provided. Applications are as varied as Molecular Viewers, Molecular Editors, Simulation Packages, Computational Chemistry Calculations, Specific Educational Resources and Programming Tools. Some free examples of every category are given, without preventing the future customer for searching for other available applications.Facultad de Ciencias ExactasCentro de Química Inorgánic

In silico and in vitro analysis of FAK/MMP signaling axis inhibition by VO-clioquinol in 2D and 3D human osteosarcoma cancer cells

The study of novel mechanisms of action of vanadium compounds is critical to elucidating the role and importance of these kinds of compounds as antitumor and antimetastatic agents. This work deals with in silico and in vitro studies of one clioquinol oxidovanadium(IV) complex [VO(clioquinol)2], VO(CQ)2, and its regulation of FAK. In particular, we focus on elucidating the relationship of the FAK inhibition, MMP activity and antimetastatic effects of the complex in human bone cancer cells.Centro de Química Inorgánic

Novel Fluoroquinolones with Possible Antibacterial Activity in Gram-Negative Resistant Pathogens: In Silico Drug Discovery

Antibiotic resistance is a global threat to public health, and the search for new antibacterial therapies is a current research priority. The aim of this in silico study was to test nine new fluoroquinolones previously designed with potential leishmanicidal activity against Campylobacter jejuni, Escherichia coli, Neisseria gonorrhoeae, Pseudomonas aeruginosa, and Salmonella typhi, all of which are considered by theWorld Health Organization to resistant pathogens of global concern, through molecular docking and molecular dynamics (MD) simulations using wild-type (WT) and mutanttype (MT) DNA gyrases as biological targets. Our results showed that compound 9FQ had the best binding energy with the active site of E. coli in both molecular docking and molecular dynamics simulations. Compound 9FQ interacted with residues of quinolone resistance-determining region (QRDR) in GyrA and GyrB chains, which are important to enzyme activity and through which it could block DNA replication. In addition to compound 9FQ, compound 1FQ also showed a good affinity for DNA gyrase. Thus, these newly designed molecules could have antibacterial activity against Gram-negative microorganisms. These findings represent a promising starting point for further investigation through in vitro assays, which can validate the hypothesis and potentially facilitate the development of novel antibiotic drugs.Centro de Química Inorgánic

Vanillin enones as selective inhibitors of the cancer associated carbonic anhydrase isoforms IX and XII: the out of the active site pocket for the design of selective inhibitors?

New C-glycosides and α,β-unsaturated ketones incorporating the 4-hydroxy-3-methoxyphenyl (vanillin) moiety as inhibitors of carbonic anhydrase (CA, EC 4.2.1.1) isoforms have been investigated. The inhibition profile of these compounds is presented against four human CA (hCA) isozymes, comprising hCAs I and II (cytosolic, ubiquitous enzymes) and hCAs IX and XII (tumour associated isozymes). Docking analysis of the inhibitors within the active sites of these enzymes has been performed and is discussed, showing that the observed selectivity could be explained in terms of an alternative pocket out of the CA active site where some of these compounds may bind. Several derivatives were identified as selective inhibitors of the tumour-associated hCA IX and XII. Their discovery might be a step in the strategy for finding an effective non-sulfonamide CA inhibitor useful in therapy/diagnosis of hypoxic tumours or other pathologies in which CA isoforms are involved.Centro de Estudios de Compuestos OrgánicosCentro de Química Inorgánic