Introducción a la Química Medicinal

Este primer libro de Química Medicinal de la carrera de Farmacia de la Facultad de Ciencias Exactas, no solo será materia de lectura para sus estudiantes, sino que también será de utilidad para todos aquellos que estén interesados en conocer las diferentes metodologías de las que hace uso la Química Medicinal hoy, describiendo las áreas que contribuyen para la obtención de nuevos fármacos. Siempre se planteó que era necesario que nuestros alumnos tuvieran un material acorde a los conocimientos actuales y que les permitiera ver una perspectiva del farmacéutico en el diseño de nuevos fármacos, construyendo nuevas moléculas para contribuir a mejorar las diferentes patologías que afectan a nuestra sociedad. Los autores abordan, como objetivo fundamental, el descubrimiento de nuevos fármacos con un profundo conocimiento de las metodologías que explican y usan, tratando de transmitir, con ejemplos y conclusiones, que los lectores pueden sentirse partícipes activos de la creación de nuevos conocimientos.Facultad de Ciencias Exacta

Docking Applied to the Study of Inhibitors of c-Met Kinase

Quinoxaline derivatives were studied as inhibitors of c-Met kinase, a receptor associated with high tumor grade and poor prognosis in a number of human cancers. In this paper we used docking methodologies to predict the binding conformation of a set of quinoxalines and to explain the differences of biological activities previously reported.Facultad de Ciencias Exacta

Docking Applied to the Study of Inhibitors of c-Met Kinase

Quinoxaline derivatives were studied as inhibitors of c-Met kinase, a receptor associated with high tumor grade and poor prognosis in a number of human cancers. In this paper we used docking methodologies to predict the binding conformation of a set of quinoxalines and to explain the differences of biological activities previously reported.Facultad de Ciencias Exacta

Kinetic study of benzyl sulfamide synthesis by thermolysis of N‐(benzyl)‐N´‐(tert butoxycarbolyl) sulfamide

In this investigation, a kinetic study of the thermolysis of N-(benzyl)-N´-(tert-butoxycarbonyl) sulfamide to yield benzylsulfamide in an efficient manner was performed. The thermolysis reaction was monitored in helium flow by thermogravimetry at different heating rates between 0.2 and 10 oC/min. The activation energy value was obtained from the Kissinger-Akahira-Sunose isoconversional method and theoretical calculations (from Transition State Theory). The reaction model of the process was studied by means of the master-plot method. Results obtained from experiments of thermolysis performed under the melting point temperature of N-(benzyl)-N´-(tert-butoxycarbonyl) sulfamide fit with an Avrami-Erofeev model whereas data found for experiments at higher temperatures fit with first order model. Isothermal experiments were simulated at 115, 120 and 130 oC using the model-free method, employing only the activation energy value.Facultad de Ciencias Exacta

Kinetic study of benzyl sulfamide synthesis by thermolysis of N-(benzyl)-N´-(tert-butoxycarbolyl) sulfamide

In this investigation, a kinetic study of the thermolysis of N-(benzyl)-N´-(tert-butoxycarbonyl) sulfamide to yield benzylsulfamide in an efficient manner was performed. The thermolysis reaction was monitored in helium flow by thermogravimetry at different heating rates between 0.2 and 10 oC/min. The activation energy value was obtained from the Kissinger-Akahira-Sunose isoconversional method and theoretical calculations (from Transition State Theory). The reaction model of the process was studied by means of the master-plot method. Results obtained from experiments of thermolysis performed under the melting point temperature of N-(benzyl)-N´-(tert-butoxycarbonyl) sulfamide fit with an Avrami-Erofeev model whereas data found for experiments at higher temperatures fit with first order model. Isothermal experiments were simulated at 115, 120 and 130 oC using the model-free method, employing only the activation energy value

Kinetic study of benzyl sulfamide synthesis by thermolysis of N‐(benzyl)‐N´‐(tert butoxycarbolyl) sulfamide

In this investigation, a kinetic study of the thermolysis of N-(benzyl)-N´-(tert-butoxycarbonyl) sulfamide to yield benzylsulfamide in an efficient manner was performed. The thermolysis reaction was monitored in helium flow by thermogravimetry at different heating rates between 0.2 and 10 oC/min. The activation energy value was obtained from the Kissinger-Akahira-Sunose isoconversional method and theoretical calculations (from Transition State Theory). The reaction model of the process was studied by means of the master-plot method. Results obtained from experiments of thermolysis performed under the melting point temperature of N-(benzyl)-N´-(tert-butoxycarbonyl) sulfamide fit with an Avrami-Erofeev model whereas data found for experiments at higher temperatures fit with first order model. Isothermal experiments were simulated at 115, 120 and 130 oC using the model-free method, employing only the activation energy value.Facultad de Ciencias Exacta

Searching for New Leads to Treat Epilepsy: Target-Based Virtual Screening for the Discovery of Anticonvulsant Agents

The purpose of this investigation is to contribute to the development of new anticonvulsant drugs to treat patients with refractory epilepsy. We applied a virtual screening protocol that involved the search into molecular databases of new compounds and known drugs to find small molecules that interact with the open conformation of the Nav1.2 pore. As the 3D structure of human Nav1.2 is not available, we first assembled 3D models of the target, in closed and open conformations. After the virtual screening, the resulting candidates were submitted to a second virtual filter, to find compounds with better chances of being effective for the treatment of P-glycoprotein (P-gp) mediated resistant epilepsy. Again, we built a model of the 3D structure of human P-gp, and we validated the docking methodology selected to propose the best candidates, which were experimentally tested on Nav1.2 channels by patch clamp techniques and in vivo by the maximal electroshock seizure (MES) test. Patch clamp studies allowed us to corroborate that our candidates, drugs used for the treatment of other pathologies like Ciprofloxacin, Losartan, and Valsartan, exhibit inhibitory effects on Nav1.2 channel activity. Additionally, a compound synthesized in our lab, N,N′-diphenethylsulfamide, interacts with the target and also triggers significant Na1.2 channel inhibitory action. Finally, in vivo studies confirmed the anticonvulsant action of Valsartan, Ciprofloxacin, and N,N′-diphenethylsulfamide.Fil: Palestro, Pablo Hernán. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Cátedra de Química Medicinal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Enrique, Nicolás Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Goicoechea, Sofia. 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: Villalba, Maria Luisa. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Cátedra de Química Medicinal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Sabatier, Laureano Leonel. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Cátedra de Química Medicinal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Martín, Pedro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Milesi, Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Bruno Blanch, Luis Enrique. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Cátedra de Química Medicinal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gavernet, Luciana. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Cátedra de Química Medicinal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Docking Applied to the Study of Inhibitors of c-Met Kinase

Quinoxaline derivatives were studied as inhibitors of c-Met kinase, a receptor associated with high tumor grade and poor prognosis in a number of human cancers. In this paper we used docking methodologies to predict the binding conformation of a set of quinoxalines and to explain the differences of biological activities previously reported.Facultad de Ciencias Exacta

Strengths and Weaknesses of Docking Simulations in the SARS-CoV-2 Era: The Main Protease (Mpro) Case Study

The scientific community is working against the clock to arrive at therapeutic interventions to treat patients with COVID-19. Among the strategies for drug discovery, virtual screening approaches have the capacity to search potential hits within millions of chemical structures in days, with the appropriate computing infrastructure. In this article, we first analyzed the published research targeting the inhibition of the main protease (Mpro), one of the most studied targets of SARS-CoV-2, by docking-based methods. An alarming finding was the lack of an adequate validation of the docking protocols (i.e., pose prediction and virtual screening accuracy) before applying them in virtual screening campaigns. The performance of the docking protocols was tested at some level in 57.7% of the 168 investigations analyzed. However, we found only three examples of a complete retrospective analysis of the scoring functions to quantify the virtual screening accuracy of the methods. Moreover, only two publications reported some experimental evaluation of the proposed hits until preparing this manuscript. All of these findings led us to carry out a retrospective performance validation of three different docking protocols, through the analysis of their pose prediction and screening accuracy. Surprisingly, we found that even though all tested docking protocols have a good pose prediction, their screening accuracy is quite limited as they fail to correctly rank a test set of compounds. These results highlight the importance of conducting an adequate validation of the docking protocols before carrying out virtual screening campaigns, and to experimentally confirm the predictions made by the models before drawing bold conclusions. Finally, successful structure-based drug discovery investigations published during the redaction of this manuscript allow us to propose the inclusion of target flexibility and consensus scoring as alternatives to improve the accuracy of the methods.Fil: Llanos, Manuel. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Gantner, Melisa Edith. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Rodríguez, Santiago. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Alberca, Lucas Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Bellera, Carolina Leticia. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Talevi, Alan. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Gavernet, Luciana. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentin

Synthesis of anticonvulsant sulfamides: theoretical study of the related mechanism

A theoretical study of the mechanisms associated with the synthesis of anticonvulsant symmetric N,N’-substituted sulfamides is presented. Two possible synthetic routes are compared, which mainly differ in the use of pyridine as a nucleophilic agent in the reaction mechanism. Geometry optimization techniques and transition-state detection at the B3LYP/6-31G** level, modeling the solvent by means of an isodensity polarizable continuum approach, allow the most suitable method for the experimental process to be discerned.Facultad de Ciencias Exacta