Estudos de Target Fishing de 5nitroheterociclo benzidrazidas
Data
2018-06-21
Autores
Santos, Paloma Freire dos 
Orientadores
Rando, Daniela Gonçales Galasse
Tipo
Trabalho de conclusão de curso
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Compostos 5nitroheterociclo benzidrazídicos são moléculas de interesse no
desenvolvimento de antiparasitários para doenças negligenciadas, mas que, contudo, ainda
são pouco exploradas para outras potencialidades biológicas.
Com vistas a encontrar novas aplicações para estes compostos, o trabalho teve como objetivo
estudos de modelagem molecular capazes de apontar potenciais alvos macromoleculares do
organismo humano, com os quais estes derivados poderiam interagir. Para tanto, empregouse duas abordagens de docking molecular: a direta e a indireta, esta última também conhecida
como Target Fishing. Uma série de dezesseis 5nitroheterociclo benzidrazidas foi empregada.
Docking reverso foi realizado empregandose o programa Pharmmapper. Para cada composto
foi gerada uma tabela de potenciais alvos sendo, ao final, tais tabelas comparadas em busca
de alvos coincidentes e com valores de z'score significativos. O melhor alvo comum à série
foi a Proteína Tirosina Fosfatase 1B que pertence à família das fosfatases PTPs, conhecidas
por desfosforilar e controlar a multiplicidade da sinalização em eventos como crescimento,
diferenciação, apoptose e movimento celular. A PTP1B é um regulador negativo na
sinalização de insulina e, por isso, atrativo alvo no tratamento de Diabetes tipo II. Os
compostos GPQF07 e 12 apresentaram os melhores valores de z'score (3,23 e 3,22,
respectivamente) e padrão de interação envolvendo oito interações totais sendo cinco
interações de hidrogênio, e três hidrofóbicas. Estudos de docking direto foram realizados com
o GPQF07 bem como com o GPQF38, o qual mostrou valor de z’score negativo e com
GPQF64 que, por sua vez, corresponde ao derivado não substituído e que apresentou
z’score menor que 1. Os resultados mostraram que GPQF07 apresentou padrão de interação
com o alvo similar ao revelado nos estudos de docking reverso. Já os GPQF38 e 64
ancoraramse de forma diversa à observada para o 07. Interações com Asp48 e Arg221
parecem ser significativas para o reconhecimento pela PTP1B bem como o posicionamento
dos anéis aromáticos entre duas regiões hidrofóbicas. Este padrão foi relatado na literatura
por COMBS e RAKSE et al. como interações importantes para conferir seletividade e potencial
contra a PTP1B. O mesmo padrão foi observado para GPQF07 e 64, enquanto 38 não
apresentou todas estas características. A diferença entre GPQF07 e 64 parece estar
relacionada com as interações hidrofóbicas. Estes resultados indicam porque GPQF07 seria
um potencial bom ligante da PTP1B.
5Nitroheterocyclic benzhydrazides constitute a chemical class of compounds which has been widely explored in searching for new antiparasitic drugs but; however, they have been poorly explored to other therapeutic applications. Aiming to fulfill this lack of information, in this project we employed molecular modeling approaches to find out new potential human macromolecular targets to this class of compounds, which could be explored in the treatment of different human diseases. Molecular reverse docking, also known as Target Fishing, allows finding new macromolecular targets for ligands with known chemical structures by screening pharmacophore data banks. In this work we searched these data banks for new potential targets to sixteen 5nitroheterocyclic benzhydrazides, through employing the Pharmmapper webbased software. To each compound the results were ranked according to their z’score value as well as compared to find out the common targets to the series. The best common target was the Protein Tyrosine Phosphatase 1B, a protein which belongs to the family of phosphatases PTPs, this protein is responsible for dephosphorylation processes which control several events such as cell growth, differentiation, apoptosis, and movement. PTP1B is a negative regulator in insulin signaling, therefore, an attractive target in the treatment of Type II Diabetes. GPQF07 and 12 presented the best zscore values (3.23 and 3.22, respectively) and interaction pattern involving eight total interactions (five hydrogen bonds and three hydrophobic interactions). Direct docking studies were, then, performed with GPQF07 and 38, this later presenting a negative z’score value. A nonsubstituted derivative, the GPQF64, was also studied through molecular docking to understand the contributions of the substituent to the class behavior. This compound presented z’score<1. GPQF07 presented interactions with Asp48 and Arg221 as well as positioned its benzene ring between two hydrophobic regions of PTP1B. These interactions were described by COMBS and RAKSE et al. as important to the recognition by the target and action selectivity. The same interaction pattern was observed with GPQF64; GPQF38; however, presented a different conformation within the binding site, lacking one or more of the important interactions. The difference between GPQF07 and 64 seems to rely on the hydrophobic interactions within the recognition site. These results are consistent with the findings of Pharmmapper and justify why GPQF07 was presented as a potential good ligand of PTP1B.
5Nitroheterocyclic benzhydrazides constitute a chemical class of compounds which has been widely explored in searching for new antiparasitic drugs but; however, they have been poorly explored to other therapeutic applications. Aiming to fulfill this lack of information, in this project we employed molecular modeling approaches to find out new potential human macromolecular targets to this class of compounds, which could be explored in the treatment of different human diseases. Molecular reverse docking, also known as Target Fishing, allows finding new macromolecular targets for ligands with known chemical structures by screening pharmacophore data banks. In this work we searched these data banks for new potential targets to sixteen 5nitroheterocyclic benzhydrazides, through employing the Pharmmapper webbased software. To each compound the results were ranked according to their z’score value as well as compared to find out the common targets to the series. The best common target was the Protein Tyrosine Phosphatase 1B, a protein which belongs to the family of phosphatases PTPs, this protein is responsible for dephosphorylation processes which control several events such as cell growth, differentiation, apoptosis, and movement. PTP1B is a negative regulator in insulin signaling, therefore, an attractive target in the treatment of Type II Diabetes. GPQF07 and 12 presented the best zscore values (3.23 and 3.22, respectively) and interaction pattern involving eight total interactions (five hydrogen bonds and three hydrophobic interactions). Direct docking studies were, then, performed with GPQF07 and 38, this later presenting a negative z’score value. A nonsubstituted derivative, the GPQF64, was also studied through molecular docking to understand the contributions of the substituent to the class behavior. This compound presented z’score<1. GPQF07 presented interactions with Asp48 and Arg221 as well as positioned its benzene ring between two hydrophobic regions of PTP1B. These interactions were described by COMBS and RAKSE et al. as important to the recognition by the target and action selectivity. The same interaction pattern was observed with GPQF64; GPQF38; however, presented a different conformation within the binding site, lacking one or more of the important interactions. The difference between GPQF07 and 64 seems to rely on the hydrophobic interactions within the recognition site. These results are consistent with the findings of Pharmmapper and justify why GPQF07 was presented as a potential good ligand of PTP1B.