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Estudo farmacofórico sobre isomanídeos peptidomiméticos inibidores das calicreínas teciduais humanas 5 e 7CalicreínaIsomanideoDocking molecularDFTFarmacóforoKallikreinIsomannideMolecular dockingDFTPharmacophoreCiências BiológicasAs quinze calicreínas teciduais humanas (KLKs) são endopeptidases, cujos genes pertencem ao maior cluster ininterrupto de enzimas do genoma, e nomeadas de 1 a 15 de acordo com sua ordem de descoberta. Apesar do domínio catalítico comum (serino-protease), as calicreínas possuem relativamente pouca relação filogenética com a calicreína plasmática e compartilham a conservada tríade de resíduos catalíticos da família a qual pertencem, His57, Asp102 e Ser195. Mas é segundo a natureza do resíduo 189 (representante do subsítio S1 do sítio ativo), que suas atividades (preferências por diferentes substratos) são classificadas em quimotripsina-símile ou tripsina-símile. As KLKs humanas podem ser subdivididas em vários grupos tecido-específicos, os quais cumprem inúmeras tarefas ao longo da vida. Distúrbios concomitantes à regulação alterada de suas atividades variam de acordo com local onde seus genes são expressos. As KLKs 5 e 7 apresentam atividade tríptica e quimotríptica respectivamente. São normalmente encontradas em vários tecidos, porém ambas são especificamente abundantes nas camadas granular e espinhosa da epiderme, onde degradam as proteínas do corneodesmossomos, levando à descamação. Além de desempenhar papéis em desordens da pele como dermatite atópica, psoríase e síndrome de Netherton, podem digerir vários componentes da matriz extracelular, contribuindo para a disseminação metastática de células tumorais em vários tipos de cânceres, como o carcinoma ovariano epitelial e pancreático. As KLKs são muitas vezes mantidas inibidas por uma variedade de inibidores endógenos, que, em equilíbrio fino com a atividade enzimática são essenciais para a homeostase tecidual. Várias estratégias vêm sendo aplicadas visando o projeto de inibidores de serino-proteases. Isomanídeos são compostos originados da desidratação do D-manitol, que apresentam uma estrutura bicíclica característica. Em nosso trabalho, foi feito um estudo farmacofórico computacional com compostos derivados de isomanídeos, divididos em duas séries: amidas e ésteres. Em vista de resultados experimentais prévios, sabia-se que o mecanismo de inibição desses compostos varia de reversível competitiva a reversível não competitiva. A busca através do servidor CASTp, apontou os prováveis exossítios de interação para a KLK5 e KLK7, os quais, juntamente com os sítios ativos, serviram de bolsões receptores dos compostos separadamente, pelo método de docking molecular. As posições gerais dos inibidores nas docagens não foram significativamente próximas daquelas nos testes cinéticos, o que já era esperado. A análise da variação das conformações segundo os ângulos de torção também não pode contribuir para uma padronização das afinidades dos isomanídeos, devido à sua liberdade conformacional. Porém, observou-se que o inibidor não-competitivo AM04 apresentou escore relativamente alto em um dos exossítios encontrados, mais provável de influenciar conformacionalmente a disposição dos resíduos do sitio ativo da KLK5. O outro composto não-competitivo, AM05, apresentou menor score para o exossítio de maior identidade com o sítio ativo e score alto para os demais. Este achado principalmente corrobora com provável presença de um ou vários sítios com significativa atividade alostérica na superfície da enzima, o que, com maiores estudos, pode ser estendido à KLK7 e demais calicreínas. Além disso, os cálculos DFT, da estrutura eletrônica dos inibidores, mostraram que, na KLK5, o HOMO da AM04 e LUMO da AM05 estão correlacionados às suas interações com os sítios alostéricos. A abordagem de outros métodos de predição, como dinâmica molecular, possibilitariam maiores detalhes sobre a influência desses ligantes no comprometimento ou não da abertura e capacidade de acomodação de outros compostos nos sítios ativos, essencialmente da KLK5. O desenvolvimento de inibidores para KLK5 e KLK7 pode ainda ajudar a elucidar os papéis fisiopatológicos das calicreínas e no projeto de novos inibidores.The fifteen human tissue kallikrein (KLKs) are endopeptidases, whose genes belong to the largest uninterrupted cluster of enzymes in genome, and named 1-15 according to their order of discovery. Despite the common catalytic domain (serine protease), they have relatively little phylogenetic relationship with plasma kallikrein. They share the conserved catalytic triad residues of the family to which they belong, His57, Asp102 and Ser195. However, their activities (preference for different substrates) are classified according to the nature of the residue 189 (representative of the S1 subsite of the active site), as chymotrypsin-like or trypsin-like. Human KLKs can be subdivided into various tissue-specific groups, which fulfill numerous tasks throughout life. Disorders that occur due altered regulation of kallikreins activities vary according to where their genes are expressed. KLK5 and 7 present tryptic and quimotryptic activities, respectively. Both are usually found in many tissues, but they are specifically abundant in spinous and granular layers of the epidermis, where they degrade the proteins of corneodesmossomos, leading to desquamation. In addition to playing role in skin disorders such as atopic dermatitis, psoriasis and Netherton's syndrome, the two enzymes are able to digest multiple components of the extracellular matrix, leading to metastatic spread of tumor cells in various types of cancers such as epithelial ovarian carcinoma and pancreatic adenocarcinoma. KLKs are often maintained inhibited by a variety of endogenous inhibitors, whichare in fine equilibrium with the enzymatic activity, essential for tissue homeostasis. Several strategies have been applied in order to design inhibitors to serine proteases. Isomannides are compounds derived from D-mannitol dehydration, which possess a characteristic bicyclic structure. In our work, a computational pharmacophoric study was done with compounds derived from isomannide, divided into two series: amides and esters. In view of previous experimental results, it was known that the mechanism of inhibition of those compounds range from reversible competitive to reversible non-competitive. The search through CASTp online server pointed probable exosites for interaction in KLK5 and KLK7. Such exosites, in addition to the active sites, were used as receptor pockets for the compounds separately by molecular docking method. General positions of the docking inhibitors were not significantly close to those in the kinetic assays. That result was expected. Conformational analysis of torsion angles didn’t contribute to standardization of isomannides affinities to receptors, mainly due the large conformational freedom of those compounds. In other hand, it was observed that the non-competitive inhibitor, AM04 showed relatively high score in one exosite, topographically more likely to influence conformation disposition of the active site residues of KLK5. The other non-competitive compound, AM05, showed lower score for the exosite of greater identity with the active site, and score high for the others allosteric pockets. That result corroborates with probable presence of one or several allosteric sites with significant activity on the enzyme surface, whichcan be extended to other kallikreins and KLK7 through further studies. Additionally, electronic structure DFT calculations of inhibitors showed that, in KLK5, the HOMO of AM04 and LUMO of AM05 are favorably correlated to their interactions with allosteric sites. Other prediction methods approach, such as molecular dynamics, would give details about the influence of those ligands involvement in accommodation of other compounds in the active sites, primarily in KLK5. The development of inhibitors for KLK5 and KLK7 may also help elucidate the pathophysiological roles of kallikrein and the designing of new drugs.Universidade Federal do Triângulo MineiroInstituto de Ciências da Saúde - ICS::Curso de MedicinaBrasilUFTMCurso de Pós-Graduação em Ciências FisiológicasABRAHÃO Júnior, Odonírio85382671672http://lattes.cnpq.br/4202309588377295SILVA, Fernando Freitas Siqueira2015-12-10T13:53:40Z2013-12-20info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfapplication/pdfSILVA, Fernando Freitas Siqueira. Estudo farmacofórico sobre isomanídeos peptidomiméticos inibidores das calicreínas teciduais humanas 5 e 7. 2013. 95f. Dissertação(Mestrado em Ciências Fisiológicas) - Curso de Pós-Graduação em Ciências Fisiológicas, Universidade Federal do Triângulo Mineiro, Uberaba, 2013.http://bdtd.uftm.edu.br/handle/tede/182porAdvanced Chemistry Development I. ChemSketch 12.0. Toronto; 2013. 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Journal of Physical Chemistry A. 2007;111(8):1554-61.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da UFTMinstname:Universidade Federal do Triangulo Mineiro (UFTM)instacron:UFTM2019-06-26T20:05:32Zoai:bdtd.uftm.edu.br:tede/182Biblioteca Digital de Teses e Dissertaçõeshttp://bdtd.uftm.edu.br/PUBhttp://bdtd.uftm.edu.br/oai/requestbdtd@uftm.edu.br||bdtd@uftm.edu.bropendoar:2024-04-24T09:59:59.010078Biblioteca Digital de Teses e Dissertações da UFTM - Universidade Federal do Triangulo Mineiro (UFTM)false
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