Estudos computacionais e síntese de derivados sulfonamídicos candidatos a inibidores da enzima sn-1-diacilglicerol lipase alfa (DAGL-alfa) para o tratamento da obesidade
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Data
2019-08-28
Autores
Ribeiro, Thaíz Rosa
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Universidade Estadual Paulista (Unesp)
Resumo
Segundo dados da Organização Mundial da Saúde, cerca de 13% da população mundial é classificada como obesa (2016). Consequentemente, há um elevado gasto em saúde para os cofres públicos e para a população de modo geral, visto que a obesidade é uma doença multifatorial, a qual está diretamente relacionada com doenças cardiometabólicas. O tratamento da obesidade pode ser realizado com reeducação alimentar, atividade física regular e psicoterapia, mas quando há distúrbios metabólicos/psicológicos e/ou elevados riscos cardiometabólicos, se fazem necessárias intervenções medicamentosa e cirúrgica. Uma alternativa aos tratamentos atualmente utilizados é modular o Sistema Endocanabinóide, através da inibição da enzima sn-1-Diacilglicerol lipase α (DAGL-α), principal responsável pela produção de 2-araquidonoilglicerol (2-AG), que é diretamente responsável pela ativação de receptores CB1, que por sua vez, tem como função o controle do apetite, contornando assim os efeitos adversos observados na atuação direta sobre o receptor em questão. No presente projeto de pesquisa foram realizados estudos computacionais e a síntese de novos derivados sulfonamídicos candidatos a inibidores da enzima DAGL-α. A etapa de estudos in silico da enzima DAGL-α e dos derivados sulfonamídicos propostos, foi realizada por meio da abordagem SBDD (structure-based drug design), visando compreender os requisitos estruturais necessários para a atividade inibitória, uma vez que se busca inibição competitiva, e finalmente a triagem virtual de 84 compostos planejados. Nesse contexto, foi realizada a validação e análise meticulosa do modelo empregando a enzima Penicillium camembertti lipase (PCL), dada a indisponibilidade da estrutura cristalográfica de DAGL-α humana, utilizando substâncias da literatura com atividades in vitro conhecidas. Após avaliação das quatro funções de pontuação pertencentes ao programa GOLD (GoldScore, ChemScore, ChemPLP e ASP), observou-se que a função ASP forneceu a predição de interações com potencial capacidade de discernir ligantes ativos e inativos, propiciando a seleção de 8 compostos com promissora atividade inibitória frente à enzima DAGL-α para a etapa de síntese. Dentre eles, 3 substâncias foram obtidas com elevado grau de pureza através de uma única etapa e os outros 2 compostos por meio de 4 etapas de reação, envolvendo irradiação por micro-ondas na última etapa.
According to the World Health Organization (WHO), ca. 13% of the world population can be classified as obese (2016). Consequently, the government expenses regarding to health of population are high, because obesity is a multifactorial disease, which is directly related with cardiometabolic diseases. The treatment of obesity can be conducted through changes in food intake, practice of physical activities regularly and psychotherapy, however when metabolic or psychological disturbs and/or increased cardiometabolic risks, approaches related with the use of drugs and/or surgery are required. An alternative to replace the current treatments is the modulation of the Endocannabinoid System, through the inhibition of the sn-1-diacylglycerol lipase alpha (DAGL-alpha), the main character for the production of 2-arachidonoylglycerol (2-AG), which is directly responsible by the activation of CB1 receptors. Then, the modulation of CB1 can control appetite, avoiding deleterious effects observed when bioactive compounds modulate CB1 directly. In this research project were performed computational studies and synthesis of novel sulfonamide candidate inhibitors of the enzyme DAGL-α. The step of an in silico study of DAGL-α and bioactive compounds retrieved from literature was performed by SBDD approach (structure-based drug design), to understand the required structural features for the inhibitory activity, followed by Structure Based Virtual Screening (SBVS) of the novel designed derivatives. In this context, the validation and detailed assessment of a in silico model is necessary, by using Penicillium Camembertti lipase (PCL), because of the unavailability of the crystallographic structure of human DAGL-α. After assessing the four scoring functions belonging to the GOLD program (GoldScore, ChemScore, ChemPLP and ASP), it was observed that ASP scoring function provided the prediction of interactions with potential ability to discriminate active and inactive ligands, allowing the selection of 8 compounds with promising inhibitory activity against the DAGL-α enzyme for the synthesis step. Among them, 3 substances were obtained with a high degree of purity through a single step and the other 2 compounds were obtained by 4 reaction steps, involving microwave irradiation in the last step.
According to the World Health Organization (WHO), ca. 13% of the world population can be classified as obese (2016). Consequently, the government expenses regarding to health of population are high, because obesity is a multifactorial disease, which is directly related with cardiometabolic diseases. The treatment of obesity can be conducted through changes in food intake, practice of physical activities regularly and psychotherapy, however when metabolic or psychological disturbs and/or increased cardiometabolic risks, approaches related with the use of drugs and/or surgery are required. An alternative to replace the current treatments is the modulation of the Endocannabinoid System, through the inhibition of the sn-1-diacylglycerol lipase alpha (DAGL-alpha), the main character for the production of 2-arachidonoylglycerol (2-AG), which is directly responsible by the activation of CB1 receptors. Then, the modulation of CB1 can control appetite, avoiding deleterious effects observed when bioactive compounds modulate CB1 directly. In this research project were performed computational studies and synthesis of novel sulfonamide candidate inhibitors of the enzyme DAGL-α. The step of an in silico study of DAGL-α and bioactive compounds retrieved from literature was performed by SBDD approach (structure-based drug design), to understand the required structural features for the inhibitory activity, followed by Structure Based Virtual Screening (SBVS) of the novel designed derivatives. In this context, the validation and detailed assessment of a in silico model is necessary, by using Penicillium Camembertti lipase (PCL), because of the unavailability of the crystallographic structure of human DAGL-α. After assessing the four scoring functions belonging to the GOLD program (GoldScore, ChemScore, ChemPLP and ASP), it was observed that ASP scoring function provided the prediction of interactions with potential ability to discriminate active and inactive ligands, allowing the selection of 8 compounds with promising inhibitory activity against the DAGL-α enzyme for the synthesis step. Among them, 3 substances were obtained with a high degree of purity through a single step and the other 2 compounds were obtained by 4 reaction steps, involving microwave irradiation in the last step.
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Palavras-chave
Obesidade, DAGL-alfa, Sulfonamidas, Receptor CB1, Sistema endocanabinóide, Ancoragem molecular, Triagem virtual, Planejamento racional e síntese