RESUMO
Aedes aegypti mosquitoes transmit several human pathogens that cause millions of deaths worldwide, mainly in Latin America. The indiscriminate use of insecticides has resulted in the development of species resistance to some such compounds. Piperidine, a natural alkaloid isolated from Piper nigrum, has been used as a hit compound due to its larvicidal activity against Aedes aegypti. In the present study, piperidine derivatives were studied through in silico methods: pharmacophoric evaluation (PharmaGist), pharmacophoric virtual screening (Pharmit), ADME/Tox prediction (Preadmet/Derek 10.0®), docking calculations (AutoDock 4.2) and molecular dynamics (MD) simulation on GROMACS-5.1.4. MP-416 and MP-073 molecules exhibiting ΔG binding (MMPBSA -265.95 ± 1.32 kJ/mol and -124.412 ± 1.08 kJ/mol, respectively) and comparable to holo (ΔG binding = -216.21 ± 0.97) and pyriproxyfen (a well-known larvicidal, ΔG binding= -435.95 ± 2.06 kJ/mol). Considering future in vivo assays, we elaborated the theoretical synthetic route and made predictions of the synthetic accessibility (SA) (SwissADME), lipophilicity and water solubility (SwissADME) of the promising compounds identified in the present study. Our in silico results show that MP-416 and MP-073 molecules could be potent insecticides against the Aedes aegypti mosquitoes.
Assuntos
Aedes , Inseticidas , Animais , Biologia Computacional , Humanos , Inseticidas/farmacologia , Hormônios Juvenis , Larva , Piperidinas/farmacologia , Extratos Vegetais/farmacologiaRESUMO
This article presents a simplified view of integrins with emphasis on the α4 (α4ß1/VLA-4) integrin. Integrins are heterodimeric proteins expressed on the cell surface of leukocytes that participate in a wide variety of functions, such as survival, growth, differentiation, migration, inflammatory responses, tumour invasion, among others. When the extracellular matrix is degraded or deformed, cells are forced to undergo responsive changes that influence remodelling during physiological and pathological events. Integrins recognize these changes and trigger a series of cellular responses, forming a physical connection between the interior and the outside of the cell. The communication of integrins through the plasma membrane occurs in both directions, from the extracellular to the intracellular (outside-in) and from the intracellular to the extracellular (inside-out). Integrins are valid targets for antibodies and small-molecule antagonists. One example is the monoclonal antibody natalizumab, marketed under the name of TYSABRI®, used in the treatment of recurrent multiple sclerosis, which inhibits the adhesion of α4 integrin to its counter-receptor. α4ß1 Integrin antagonists are summarized here, and their utility as therapeutics are also discussed.
Assuntos
Integrina alfa4beta1 , Anticorpos Monoclonais , Adesão Celular , Integrina alfa4beta1/antagonistas & inibidores , Integrina alfa4beta1/fisiologia , LeucócitosRESUMO
Non-steroidal anti-inflammatory drugs are inhibitors of cyclooxygenase-2 (COX-2) that were developed in order to avoid the side effects of non-selective inhibitors of COX-1. Thus, the present study aims to identify new selective chemical entities for the COX-2 enzyme via molecular modeling approaches. The best pharmacophore model was used to identify compounds within the ZINC database. The molecular properties were determined and selected with Pearson's correlation for the construction of quantitative structure-activity relationship (QSAR) models to predict the biological activities of the compounds obtained with virtual screening. The pharmacokinetic/toxicological profiles of the compounds were determined, as well as the binding modes through molecular docking compared to commercial compounds (rofecoxib and celecoxib). The QSAR analysis showed a fit with R = 0.9617, R2 = 0.9250, standard error of estimate (SEE) = 0.2238, and F = 46.2739, with the tetra-parametric regression model. After the analysis, only three promising inhibitors were selected, Z-964, Z-627, and Z-814, with their predicted pIC50 (-log IC50) values, Z-814 = 7.9484, Z-627 = 9.3458, and Z-964 = 9.5272. All candidates inhibitors complied with Lipinski's rule of five, which predicts a good oral availability and can be used in in vitro and in vivo tests in the zebrafish model in order to confirm the obtained in silico data.