Navegando por Palavras-chave "Drug design"
Agora exibindo 1 - 3 de 3
Resultados por página
Opções de Ordenação
- ItemAcesso aberto (Open Access)Drug design for ever, from hype to hope(Springer, 2012-01-01) Seddon, Gavin; Lounnas, Valère; McGuire, Ross; van den Bergh, Tom; Bywater, Robert Paul; Oliveira, Laerte [UNIFESP]; Vriend, Gerrit; Radboud Univ Nijmegen; Adelard Inst; BioAxis Res; Bioprodict; Univ Oxford Magdalen Coll; Universidade Federal de São Paulo (UNIFESP)In its first 25 years JCAMD has been disseminating a large number of techniques aimed at finding better medicines faster. These include genetic algorithms, COMFA, QSAR, structure based techniques, homology modelling, high throughput screening, combichem, and dozens more that were a hype in their time and that now are just a useful addition to the drug-designers toolbox. Despite massive efforts throughout academic and industrial drug design research departments, the number of FDA-approved new molecular entities per year stagnates, and the pharmaceutical industry is reorganising accordingly. the recent spate of industrial consolidations and the concomitant move towards outsourcing of research activities requires better integration of all activities along the chain from bench to bedside. the next 25 years will undoubtedly show a series of translational science activities that are aimed at a better communication between all parties involved, from quantum chemistry to bedside and from academia to industry. This will above all include understanding the underlying biological problem and optimal use of all available data.
- ItemAcesso aberto (Open Access)Síntese e avaliação de 1-(2-(2,3-diidrobenzofuranil)metil)piperazinas potencialmente ligantes de receptores histaminérgicos H4(Universidade Federal de São Paulo, 2015-04-09) Correa, Michelle Fidelis [UNIFESP]; Fernandes, João Paulo dos Santos [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Histamine is one of the most important chemical mediators of the body. Involved in numerous physiological and pathological conditions, their effects are produced by interaction with histamine G-protein coupled receptors (GPCRs). So far it was described four histamine receptors (H1, H2, H3 and H4) differing among them in cell signaling mechanisms. Since its discovery, the H4 receptor (H4R) has been the focus of much attention. It is expressed primarily in immune cells of hematopoietic origin and, therefore has strong relationship with inflammatory and immune responses, and consequently with the pathophysiology of immuno-inflammatory disorders. Thus, the H4R is considered to be potential target for the development of new chemical entities. Considering the therapeutic potential of H4R ligands, this work aimed to synthesize 1-(2-(2,3-dihydrobenzofuranyl)methyl)piperazines inedited and evaluate their binding activity in H4R as well as H3R to analyze the selectivity towards the two receptors and obtaining compounds with increased selectivity index to H4R. Series of compounds were synthesized using iodociclization reaction, yielding 2-(iodomethyl)-2,3-dihydrobenzofuran, followed by halogen substitution with N-substituted piperazines, reaching the final compounds (LINS01001, LINS01003, LINS01004 e LINS01005). The biological activity was performed by displacement of [3H]-histamine from H3R and H4R to obtain the binding constant (Ki) from the IC50 values using the Cheng-Prussoff equation. The results indicated that the compounds had mild affinity for both receptors, exhibiting Ki values in the micromolar range. However, the compounds demonstrate different selectivity. The phenyl group, present in LINS01005, took good interaction, but non specific between the receptors (H4R Ki 28 µM; H3R Ki 17 µM)and alkyl groups give more selective H3R, as observed with compounds LINS01003 (H3R Ki 25 µM) e LINS01004 (H3R Ki 7 µM). Moreover, it was noted that the aromaticity of the core is important for good affinity to both receptor as well as the presence of a hydrophobic substituent attached at the N4-piperazine, since the molecule unsubstituted LINS01001, had the lowest affinity and Ki values for both receptor have not been determined. The results obtained in this work contribute directly to the development of new H4R ligands. It is intended to continue with future design and structural optimization of the proposed compounds to obtain higher affinity and selectivity.
- ItemSomente MetadadadosSíntese e avaliação de derivados do LINS01003 potencialmente ligantes de receptores histaminérgicos H4(Universidade Federal de São Paulo, 2017-03-27) Barbosa, Alefe Jhonatas Ramos [UNIFESP]; Fernandes, João Paulo dos Santos [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Histamine is an important chemical mediator of the organism and is related to several physiological and pathological conditions, its effects produced through interactions with histaminergic G protein coupled receptors (GPCR). To date, four histaminergic receptor subtypes (H1R, H2R, H3R and H4R) have been described differing in location and mechanism of cell signaling. Found mainly in cells of immunological and hematopoietic origin, the H4R has strong relation with inflammatory and immunological responses, therefore, it is considered a potential target for the development of new ligands with immunomodulatory activity. Its structural features, however, lead to many molecules previously described as H3R ligands to interact with the H4R because of 43% homology between these histaminergic receptor subtypes. Thus, the objective of this work was to synthesize analogues of LINS01003, dihydrobenzofurans nucleus derivatives compounds, and to evaluate the affinity of these compounds for H3 and H4 receptors. The molecules were obtained by allylation of para-substituted phenols, later isomerized by Claisen rearrangement to obtain 2-allylphenols. These were subjected to the iodocyclization reaction, generating the dihydrobenzofuran nucleus, followed by the substitution of the halogen by the N-substituted piperazine, reaching the final compounds (LINS01007, LINS01008, LINS01009 and LINS01010). Optimization studies about synthetic route were performed, with yields of approximately 80% for intermediate compounds and up to 69% for final products. Binding assays indicated moderate to low affinity for the H3R (Ki of 0.6-1.2 μM) of the molecules LINS01007 to LINS01010. As for the H4R, only LINS01007 and LINS01008 showed some affinity, (0.9 μM and 6.4 μM, respectively). The results are starting points for the development of molecules with higher affinity for the mentioned receptors.