Papers by Rolando Alberto Rodríguez Fonseca
Colloids and Surfaces B: Biointerfaces/Elsevier, 2019
Peptide epitopes have been widely used to develop synthetic vaccines and immunotherapies. However... more Peptide epitopes have been widely used to develop synthetic vaccines and immunotherapies. However, peptide epitopes may exhibit poor absorption or immunogenicity due to their low molecular weights. Conversely, fourth-generation polyamidoamine (G4-PAMAM) dendrimers are nonimmunogenic and relatively nontoxic synthetic nanoparticles that have been used as adjuvants and nanocarriers of small peptides and to improve nasal absorption. Based on this information, we hypothesized that the combination of intranasal immunization and G4-PAMAM dendrimers would be useful for enhancing the antibody responses of HIV-1 gp120 peptide epitopes. Therefore, we first used structural data, peptide epitope predictors and docking and MD simulations on MHC-II to identify two peptide epitopes on the CD4 binding site of HIV-1 gp120. The formation of G4-PAMAM-peptide complexes was evaluated in silico (molecular docking studies using different G4-PAMAM conformations retrieved from MD simulations as well as the MMGBSA approach) and validated experimentally (electrophoresis, 1H NMR and cryo-TEM). Next, the G4-PAMAM dendrimer-peptide complexes were administered intranasally to groups of female BALB/cJ mice. The results showed that both peptides were immunogenic at the systemic and mucosal levels (nasal and vaginal), and G4-PAMAM dendrimer-peptide complexes improved IgG and IgA responses in serum and nasal washes. Thus, G4-PAMAM dendrimers have potential for use as adjuvants and nanocarriers of peptides.
Journal of Anti-Cancer Agents In Medicinal Chemistry Bentham Science Publishers, 2019
Background: The epigenetic regulation of genes in cancer could be targeted by inhibiting Histone ... more Background: The epigenetic regulation of genes in cancer could be targeted by inhibiting Histone deacetylase 6 (HDAC6), an enzyme involved in several types of cancer such as lymphoma, leukemia, ovarian cancer, etc.
Objective: Through in silico methods, a set of Phenyl butyric acid derivatives with possible HDAC6 inhibitory activity were designed, rendering monophenylamides and biphenylamides using tubacin (HDAC6 selective inhibitor) as reference.
Method: The target compounds were submitted to theoretical ADMET analyses and their binding properties on different HDAC6 conformers were evaluated through docking calculations.
Results: These in silico studies allowed us to identify a compound named B-R2B. In order to have more information about the B-R2B binding recognition properties on HDAC6, the B-R2B-HDAC6 complex was submitted through 100 ns-long Molecular Dynamics (MD) simulation coupled to MMGBSA approach, revealing that B-R2B is located at the entrance of HDAC6 active pocket, blocking the passage of the substrate without reaching the HDAC6 binding site. Based on these results, B-R2B was synthesized, characterized and biologically tested. The HDAC6 fluorometric drug discovery kit Fluor-de-Lys (ENZO Life Sciences Inc.) was used to determine the HDAC6 human inhibitory activity (IC50 value) of B-R2B compound. In addition, B-R2B show IC50 values on cancer cell lines (HeLa; IC50 = 72.6 µM), acute myeloid leukemia (THP-1; IC50 = 16.5 µM), human mast leukemia (HMC; IC50 = 79.29 µM) and chronic myelogenous leukemia (Kasumi; IC50 = 101 µM).
Conclusion: These results show that B-R2B is a HDAC6 inhibitor, specifically a non-competitive type in a similar way that tubacin does, according to MD simulations.
Descripción de la publicaciónJournal of Current Pharmaceutical Design, 2017
Nanomedicine is the application of nanotechnology to medicine. This field is related to the study... more Nanomedicine is the application of nanotechnology to medicine. This field is related to the study of nanodevices and nanomaterials applied to various medical uses, such as in improving the pharmacological properties of different molecules. Dendrimers are synthetic nanoparticles whose physicochemical properties vary according to their chemical structure. These molecules have been extensively investigated as drug nanocarriers to improve drug solubility and as sustained-release systems. New therapies such as gene therapy and the development of nanovaccines can be improved by the use of dendrimers. The biophysical and physicochemical characterization of nucleic acid/peptide-dendrimer complexes is crucial to identify their functional properties prior to biological evaluation. In that sense, it is necessary to first identify whether the peptide-dendrimer or nucleic aciddendrimer complexes can be formed and whether the complex can dissociate under the appropriate conditions at the target cells. In addition, biophysical and physicochemical characterization is required to determine how long the complexes remain stable, what proportion of peptide or nucleic acid is required to form the complex or saturate the dendrimer, and the size of the complex formed. In this review, we present the latest information on characterization systems for dendrimer-nucleic acid, dendrimer-peptide and dendrimer-drug complexes with several biotechnological and pharmacological applications.
Descripción de la publicaciónJournal of Molecular Graphics and Modelling, 2017
In this work, we performed docking calculations for a set of 94 previously reported compounds on ... more In this work, we performed docking calculations for a set of 94 previously reported compounds on PAMAM of fourth generation (G4-PAMAM) to select six compounds, cromoglicic acid (CRO) − a mast cell stabilizer, Fusidic acid (FUS) − a bacteriostatic antibiotic, and Methotrexate (MTX) − a chemotherapy agent and immune system suppressant, which have the highest affinities for G4-PAMAM, and Lidocaine (LDC) − used to numb tissue in a specific area and for ventricular tachycardia treatment, Metoprolol (MET) − a β1 receptor blocker, and Pindolol (PIN) − a β blocker, which have the lowest affinities for the G4-PAMAM dendrimer, to perform MD simulations combined with the molecular mechanics generalized/Poisson-Boltzmann surface area MMGBSA/MMPBSA approach to investigate the interactions of generating 4 charge-neutral, charge-basic and charge-acid G4-PAMAM dendrimers. In addition, to validate these theoretical G4-PAMAM-drug complexes, the complexes were experimentally conjugated to determine their stability in aqueous solubility studies immediately and over one year. Our results show that among the different commercial drugs, both charged and neutral PAMAM have the most favorable binding free energies for CRO, MTX, and FUS, which appears to be due to a complex counterbalance of electrostatics and van der Waals interactions. These theoretical and aqueous solubility studies supported the high affinity of methotrexate for the G4-PAMAM-drug due to its carboxyl and aryl moieties that favor its accommodation by noncovalent interactions.
Journal of Biomolecular Structure and Dynamics, 2016
Histone deacetylases (HDACs) are a family of proteins involved in the deacetylation of histones a... more Histone deacetylases (HDACs) are a family of proteins involved in the deacetylation of histones and other non-histones substrates. HDAC6 belongs to class II and shares similar biological functions with others of its class. Nevertheless, its three-dimensional structure that involves the catalytic site remains unknown for exploring the ligand recognition properties. Therefore, in this contribution, homology modeling, 100-ns-long Molecular Dynamics (MD) simulation and docking calculations were combined to explore the conformational complexity and binding properties of the catalytic domain 2 from HDAC6 (DD2-HDAC6), for which activity and affinity toward five different ligands have been reported.
Books by Rolando Alberto Rodríguez Fonseca
Programa Iberoamericano de ciencia y tecnología para el desarrollo ISBN: 978-84-15413-50-9, 2017
Los capítulos de este libro van encaminados a la creación de nuevas terapias y fármacos dirigidos... more Los capítulos de este libro van encaminados a la creación de nuevas terapias y fármacos dirigidos frente a la infección por el VIH, basados en la nanomedicina, que juega un papel muy relevante en el cuidado de nuestra salud, a través de la generación de nuevos diagnósticos y detección rápida de enfermedad. La nanomedicina se agrupa en
nanodiagnóstico y nanoterapia, siendo su objetivo máxima curación con el mínimo daño secundario posible.
Uploads
Papers by Rolando Alberto Rodríguez Fonseca
Objective: Through in silico methods, a set of Phenyl butyric acid derivatives with possible HDAC6 inhibitory activity were designed, rendering monophenylamides and biphenylamides using tubacin (HDAC6 selective inhibitor) as reference.
Method: The target compounds were submitted to theoretical ADMET analyses and their binding properties on different HDAC6 conformers were evaluated through docking calculations.
Results: These in silico studies allowed us to identify a compound named B-R2B. In order to have more information about the B-R2B binding recognition properties on HDAC6, the B-R2B-HDAC6 complex was submitted through 100 ns-long Molecular Dynamics (MD) simulation coupled to MMGBSA approach, revealing that B-R2B is located at the entrance of HDAC6 active pocket, blocking the passage of the substrate without reaching the HDAC6 binding site. Based on these results, B-R2B was synthesized, characterized and biologically tested. The HDAC6 fluorometric drug discovery kit Fluor-de-Lys (ENZO Life Sciences Inc.) was used to determine the HDAC6 human inhibitory activity (IC50 value) of B-R2B compound. In addition, B-R2B show IC50 values on cancer cell lines (HeLa; IC50 = 72.6 µM), acute myeloid leukemia (THP-1; IC50 = 16.5 µM), human mast leukemia (HMC; IC50 = 79.29 µM) and chronic myelogenous leukemia (Kasumi; IC50 = 101 µM).
Conclusion: These results show that B-R2B is a HDAC6 inhibitor, specifically a non-competitive type in a similar way that tubacin does, according to MD simulations.
Books by Rolando Alberto Rodríguez Fonseca
nanodiagnóstico y nanoterapia, siendo su objetivo máxima curación con el mínimo daño secundario posible.
Objective: Through in silico methods, a set of Phenyl butyric acid derivatives with possible HDAC6 inhibitory activity were designed, rendering monophenylamides and biphenylamides using tubacin (HDAC6 selective inhibitor) as reference.
Method: The target compounds were submitted to theoretical ADMET analyses and their binding properties on different HDAC6 conformers were evaluated through docking calculations.
Results: These in silico studies allowed us to identify a compound named B-R2B. In order to have more information about the B-R2B binding recognition properties on HDAC6, the B-R2B-HDAC6 complex was submitted through 100 ns-long Molecular Dynamics (MD) simulation coupled to MMGBSA approach, revealing that B-R2B is located at the entrance of HDAC6 active pocket, blocking the passage of the substrate without reaching the HDAC6 binding site. Based on these results, B-R2B was synthesized, characterized and biologically tested. The HDAC6 fluorometric drug discovery kit Fluor-de-Lys (ENZO Life Sciences Inc.) was used to determine the HDAC6 human inhibitory activity (IC50 value) of B-R2B compound. In addition, B-R2B show IC50 values on cancer cell lines (HeLa; IC50 = 72.6 µM), acute myeloid leukemia (THP-1; IC50 = 16.5 µM), human mast leukemia (HMC; IC50 = 79.29 µM) and chronic myelogenous leukemia (Kasumi; IC50 = 101 µM).
Conclusion: These results show that B-R2B is a HDAC6 inhibitor, specifically a non-competitive type in a similar way that tubacin does, according to MD simulations.
nanodiagnóstico y nanoterapia, siendo su objetivo máxima curación con el mínimo daño secundario posible.