Local intersection volume (LIV) descriptors: 3D-QSAR models for PGI2 receptor ligands

Prostacyclin I2 inhibits platelet aggregation through specific binding to its membrane receptor. In this work, we developed 3D-QSAR models for a series of aromatic heterocyclic compounds from literature using the local intersection volume descriptor. The models obtained can be applied to design new PGI2 receptor ligands with potential platelet anti-aggregating activity

Synthesis, antichagasic in vitro evaluation, cytotoxicity assays, molecular modeling and SAR/QSAR studies of a 2-phenyl-3-(1-phenyl-1H-pyrazol-4-yl)-acrylic acid benzylidene-carbohydrazide series

Chagas disease (American trypanosomiasis) is one of the most important parasitic diseases with serious social and economic impacts mainly on Latin America. This work reports the synthesis, in vitro trypanocidal evaluation, cytotoxicity assays, and molecular modeling and SAR/QSAR studies of a new series of N-phenylpyrazole benzylidene-carbohydrazides. The results pointed 6k (X = H, Y = p-NO(2), pIC(50) = 4.55 M) and 6l (X = F, Y = p-CN, pIC(50) = 4.27 M) as the most potent derivatives compared to crystal violet (pIC(50) = 3.77 M). The halogen-benzylidene-carbohydrazide presented the lowest potency whereas 6l showed the most promising pro. le with low toxicity (0% of cell death). The best equation from the 4D-QSAR analysis (Model 1) was able to explain 85% of the activity variability. The QSAR graphical representation revealed that bulky X-substituents decreased the potency whereas hydrophobic and hydrogen bond acceptor Y-substituents increased it. (C) 2008 Elsevier Ltd. All rights reserved.Central Analitica do Nucleo de Pesquisas de Produtos Naturais` (NPPN, UFRJ, Brazil)FAPERJCAPESCNP

Molecular Docking Studies of Marine Diterpenes as Inhibitors of Wild-Type and Mutants HIV-1 Reverse Transcriptase

AIDS is a pandemic responsible for more than 35 million deaths. The emergence of resistant mutations due to drug use is the biggest cause of treatment failure. Marine organisms are sources of different molecules, some of which offer promising HIV-1 reverse transcriptase (RT) inhibitory activity, such as the diterpenes dolabelladienotriol (THD, IC50 = 16.5 µM), (6R)-6-hydroxydichotoma-3,14-diene-1,17-dial (HDD, IC50 = 10 µM) and (6R)-6-acetoxydichotoma-3,14-diene-1,17-dial (ADD, IC50 = 35 µM), isolated from a brown algae of the genus Dictyota, showing low toxicity. In this work, we evaluated the structure-activity relationship (SAR) of THD, HDD and ADD as anti HIV-1 RT, using a molecular modeling approach. The analyses of stereoelectronic parameters revealed a direct relationship between activity and HOMO (Highest Occupied Molecular Orbital)-LUMO (Lowest Unoccupied Molecular Orbital) gap (ELUMO–EHOMO), where antiviral profile increases with larger HOMO-LUMO gap values. We also performed molecular docking studies of THD into HIV-1 RT wild-type and 12 different mutants, which showed a seahorse conformation, hydrophobic interactions and hydrogen bonds with important residues of the binding pocket. Based on in vitro experiments and docking studies, we demonstrated that mutations have little influence in positioning and interactions of THD. Following a rational drug design, we suggest a modification of THD to improve its biological activity

Molecular Docking Studies of Marine Diterpenes as Inhibitors of Wild-Type and Mutants HIV-1 Reverse Transcriptase

AIDS is a pandemic responsible for more than 35 million deaths. The emergence of resistant mutations due to drug use is the biggest cause of treatment failure. Marine organisms are sources of different molecules, some of which offer promising HIV-1 reverse transcriptase (RT) inhibitory activity, such as the diterpenes dolabelladienotriol (THD, IC50 = 16.5 µM), (6R)-6-hydroxydichotoma-3,14-diene-1,17-dial (HDD, IC50 = 10 µM) and (6R)-6-acetoxydichotoma-3,14-diene-1,17-dial (ADD, IC50 = 35 µM), isolated from a brown algae of the genus Dictyota, showing low toxicity. In this work, we evaluated the structure-activity relationship (SAR) of THD, HDD and ADD as anti HIV-1 RT, using a molecular modeling approach. The analyses of stereoelectronic parameters revealed a direct relationship between activity and HOMO (Highest Occupied Molecular Orbital)-LUMO (Lowest Unoccupied Molecular Orbital) gap (ELUMO–EHOMO), where antiviral profile increases with larger HOMO-LUMO gap values. We also performed molecular docking studies of THD into HIV-1 RT wild-type and 12 different mutants, which showed a seahorse conformation, hydrophobic interactions and hydrogen bonds with important residues of the binding pocket. Based on in vitro experiments and docking studies, we demonstrated that mutations have little influence in positioning and interactions of THD. Following a rational drug design, we suggest a modification of THD to improve its biological activity

Anti-mycobacterial evaluation of 7-chloro-4-aminoquinolines and hologram quantitative structure-activity relationship (HQSAR) modeling of amino-imino tautomers

Submitted by Janaína Nascimento ([email protected]) on 2019-07-26T11:46:46Z No. of bitstreams: 1 ve_Bispo_Marcelle_etal_INI_2017.pdf: 17223748 bytes, checksum: 5250bb49bb35694f7440a830cf09e0a6 (MD5)Approved for entry into archive by Janaína Nascimento ([email protected]) on 2019-07-26T12:04:36Z (GMT) No. of bitstreams: 1 ve_Bispo_Marcelle_etal_INI_2017.pdf: 17223748 bytes, checksum: 5250bb49bb35694f7440a830cf09e0a6 (MD5)Made available in DSpace on 2019-07-26T12:04:36Z (GMT). No. of bitstreams: 1 ve_Bispo_Marcelle_etal_INI_2017.pdf: 17223748 bytes, checksum: 5250bb49bb35694f7440a830cf09e0a6 (MD5) Previous issue date: 2017Universidade Estadual de Londrina. Departamento de Química. Londrina, PR, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Química. Programa de Pós-Graduação em Química. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos. Rio de Janeiro. RJ, Brasil.Universidade Federal Fluminense. Ciências Aplicadas a Produtos para Saúde. Niterói, RJ, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Química. Programa de Pós-Graduação em Química. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos. Rio de Janeiro. RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Química. Programa de Pós-Graduação em Química. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos. Rio de Janeiro. RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos. Rio de Janeiro. RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Pesquisas Clínicas Evandro Chagas. Rio de Janeiro. RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Pesquisas Clínicas Evandro Chagas. Rio de Janeiro. RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos. Rio de Janeiro. RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Química. Programa de Pós-Graduação em Química. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Química. Programa de Pós-Graduação em Química. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Química. Programa de Pós-Graduação em Química. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos. Rio de Janeiro. RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Química. Programa de Pós-Graduação em Química. Rio de Janeiro, RJ, Brasil.In an ongoing research program for the development of new anti-tuberculosis drugs, we synthesized three series (A, B, and C) of 7-chloro-4-aminoquinolines, which were evaluated in vitro against Mycobacterium tuberculosis (MTB). Now, we report the anti-MTB and cytotoxicity evaluations of a new series, D (D01-D21). Considering the active compounds of series A (A01-A13), B (B01-B13), C (C01-C07), and D (D01-D09), we compose a data set of 42 compounds and carried out hologram quantitative structure-activity relationship (HQSAR) analysis. The amino-imino tautomerism of the 4-aminoquinoline moiety was considered using both amino (I) and imino (II) forms as independent datasets. The best HQSAR model from each dataset was internally validated and both models showed significant statistical indexes. Tautomer I model: leave-one-out (LOO) cross-validated correlation coefficient (q²) = 0.80, squared correlation coefficient (r²) = 0.97, standard error (SE) = 0.12, cross-validated standard error (SEcv) = 0.32. Tautomer II model: q² = 0.77, r² = 0.98, SE = 0.10, SEcv = 0.35. Both models were externally validated by predicting the activity values of the corresponding test set, and the tautomer II model, which showed the best external prediction performance, was used to predict the biological activity responses of the compounds that were not evaluated in the anti-MTB trials due to poor solubility, pointing out D21 for further solubility studies to attempt to determine its actual biological activity

Molecular Modeling Studies of the Structural, Electronic, and UV Absorption Properties of Benzophenone Derivatives

Benzophenone derivatives (BZP), an important class of organic UV filters, are widely used in sunscreen products due to their ability to absorb in the UVA and UVB ranges. The structural, electronic, and spectral properties of BZP derivatives have been studied by density functional theory (DFT) and time-dependent DFT (TD-DFT) methods. DFT/B3LYP with the 6-31G­(d) basis set is an accurate method for optimizing the geometry of BZPs. The absorption maxima obtained from the TD-DFT calculations in a vacuum were in agreement with the experimental absorption bands and showed that the main electronic transitions in the UVA/UVB range present π → π* character, the major transition being HOMO → LUMO. The oscillator strength seems to increase in the presence of disubstitution at the para position. For protic substituents, the position appears to be related to the absorption band. Absorption in the UVB range occurs in the presence of para substitution, whereas ortho substitution leads to absorption in the UVA spectral region. The obtained results provide some features for BZP derivatives that can be useful for customizing absorption properties (wavelengths and intensities) and designing new BZP derivatives as sunscreens