6 RESULTADOS E DISCUSSÃO
7. CONCLUSÕES E PERSPECTIVAS
Avaliou-se os descritores eletrônicos, estruturais e físico-químico para os compostos e observou-se a possibilidade, através dos descritores eletrônicos HOMO e LUMO, de que grupos volumosos e com mais densidade eletrônica apresentam mais interações com os resíduos His503 e Tyr545 e com o cofator FMN.
Estudos toxicológicos in silico foram realizados através de dois servidores diferentes. Ambos tiveram resultados em acordo e em desacordo com os resultados experimentais. As avaliações das atividades toxicológicas in vitro para os compostos 40a-40b e 41a-41b (Quaresma, 2015) confirmam que os compostos 40a-40b e 41a-41b não apresentaram citotoxicidade em células sanguíneas humanas in vitro. O composto 40a não apresentou genotoxicidade e os compostos 40a, 40b e 41a foram menos genotóxicos que o protótipo megazol.
Os compostos apresentaram perfil Drug-Score positivo. E embora tenham apresentado perfil Drug-Likeness negativo, todos apresentaram valores conformes à Regra de Lipinski.
Foi possível a construção de um modelo da enzima TcNTR que pode ser utilizado para estudos de interação ligante-receptor.
Os estudos de docagem molecular sugeriram que o tamanho da molécula (com substituintes no anel triazólico de até cinco carbonos), a possibilidade de interação com os resíduos His503 e Tyr545 e interações hidrofóbicas do tipo π-π com o FMN podem contribuir para a atividade de derivados nitroimidazólicos no sítio ativo da enzima nitrorredutase.
O melhor ligante planejado, PR03, encaixou-se no sítio ativo na TcNTR, projetou o grupo sulfona em direção ao cofator FMN e interagiu com os resíduos His503 e Tyr545 e com o cofator FMN. Além disso, não apresentou efeitos tóxicos, segundo o servidor Osiris, apresentou potencial genotóxico baixo para produzir um resultado de teste AMES positivo e não apresentou genotoxicidade, de acordo com o servidor ACD/ILab.
Embora os compostos tenham apresentado perfil Drug-Likeness negativo, todos apresentaram valores conformes à Regra de Lipinski.
Como perspectivas tem-se a síntese das moléculas propostas e o teste de cada uma delas frente a forma tripomastigota de T. cruzi; testes enzimáticos dos dois compostos mais ativos 41a e 41h com a nitrorredutase para estudar melhor a relação com a atividade; estudos de dinâmica molecular com a enzima nitrorredutase sem ligante e com mais tempo de simulação (até 100ns) e cálculos de energia livre com o método MM-PBSA para confirmar a relação com a atividade.
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41h), megazol e benzonidazol.
Composto HOMO LUMO
40a
40b
41a
41h), megazol e benzonidazol.
Composto HOMO LUMO
41c
41d
41e
Apêndice A - Mapas dos orbitais de fronteira HOMO e LUMO dos compostos (40a-40b e 41a- 41h), megazol e benzonidazol.
Composto HOMO LUMO
41g 41h Mega zol Benzonida zol
Apêndice D - Gráfico de Ramachandran, obtido pelo programa Procheck (Laskowski et al., 1993), para o modelo 3D de nitrorredutase tipo I de T. cruzi (construído através do servidor Swiss-Model).
Apêndice E - Gráfico de Ramachandran, obtido pelo programa Procheck (Laskowski et al., 1993), para o modelo de nitrorredutase tipo I de T. cruzi construído através do servidor I- TASSER.
1993), para o modelo de nitrorredutase tipo I de T. cruzi otimizado e refinado pelo protocolo 1: gradiente conjugado, seguido de DM/AS.
1993), para o modelo de nitrorredutase tipo I de T. cruzi otimizado e refinado pelo protocolo 2: steepest descent/gradiente conjugado, seguido por DM em meio aquoso.
Apêndice H - Distâncias das ligações hidrogênio realizadas pelos derivados nitroimidazólicos (41a, 41e, 41f, 41d e 41h), benzonidazol, nifutimox, nitrofurazona e megazol nas simulações de docagem molecular.
Ligações Hidrogênio
Composto Participantes Distância
41a 41a-O9 e HIS503-H2 O---H = 2,11 Å 41a-O8 e HIS503-H2 O---H = 3,40 Å 41a-O2 e FMN-H2 O---H = 3,75 Å 41a-N13 e TYR545-H8 N---H = 2,11 Å 41a-N14 e TYR545-H8 N---H = 2,30 Å 41d 41d-O2 e GLN549-H22 O---H = 1,84 Å 41d-O1 e GLN549-H22 O---H = 2,32 Å 41d-O2 e GLN549-H21 O---H = 3,22 Å 41d-O1 e GLN549-H21 O---H = 3,23 Å 41d-N4 e TYR545-H8 N---H = 3,85 Å 41d-N1 e TYR545-H8 N---H = 3,90 Å 41d-N10 e TYR545-H8 N---H = 3,64 Å 41d-N1 e TYR491-H7 N---H = 3,49 Å
41e 41e-O1 e HIS503-H2 O---H = 2,10 Å
Apêndice H - Distâncias das ligações hidrogênio realizadas pelos derivados nitroimidazólicos (41a, 41e, 41f, 41d e 41h), benzonidazol, nifutimox, nitrofurazona e megazol nas simulações de docagem molecular.
Ligações Hidrogênio
Composto Participantes Distância
41f 41f-O1 e HIS503-H2 O---H = 2,12 Å
41f-N13 e TYR545-H8 N---H = 3,90 Å 41h 41h-O1 e GLN549-H21 O---H = 2,68 Å 41h-O1 e GLN549-H22 O---H = 2,27 Å 41h-O2 e GLN549-H21 O---H = 2,07 Å 41h-O2 e GLN549-H22 O---H = 3,35 Å 41h-N7 e TYR545-H8 N---H = 3,21 Å 41h-N14 e TYR545-H8 N---H = 3,59 Å 41h-N1 e TYR545-H8 N---H = 3,69 Å Benzonidazol Benzonidazol-O1 e HIS503-H2 O---H = 2,20 Å Benzonidazol-O2 e HIS503-H2 O---H = 3,19 Å Benzonidazol-H10 e FMN-O4 O---H = 2,51 Å Benzonidazol-O8 e FMN-H2 O---H = 3,55 Å
(41a, 41e, 41f, 41d e 41h), benzonidazol, nifutimox, nitrofurazona e megazol nas simulações de docagem molecular.
Composto Ligações Hidrogênio
Participantes Distância Nifurtimox Nifurtimox-O2 e HIS503-H2 O---H = 3,01 Å
Nifurtimox-O1 e ARG140-H2 O---H = 1,78 Å Nifurtimox-O1 e ARG140-H3 O---H = 3,21 Å Nifurtimox-O13 eFMN-H2 O---H = 3,72 Å Nifurtimox-O10 e GLN549-H22 O---H = 1,86 Å Nifurtimox-O10 e GLN549-H21 O---H = 2,76 Å Nifurtimox-O9 eFMN-H2 O---H = 3,57 Å Nitrofurazona Nitrofurazona-O3 e GLN549-H22 O---H = 3,81 Å Nitrofurazona-O3 e GLN549-H21 O---H = 3,08 Å Nitrofurazona-N2 e TYR545-H8 N---H = 3,75 Å Nitrofurazona-H7 e ALA430-O6 O---H = 2,69 Å Nitrofurazona-H6 e ALA430-O6 O---H = 2,46 Å Nitrofurazona-H7 e FMN-O2 O---H = 3,59 Å Nitrofurazona-H6 e FMN-O2 O---H = 3,65 Å
(41a, 41e, 41f, 41d e 41h), benzonidazol, nifutimox, nitrofurazona e megazol nas simulações de docagem molecular.
Composto Ligações Hidrogênio
Participantes Distância Megazol Megazol-N4 e TYR545-H8 N---H = 3,06 Å
Megazol-S11 e TYR545-H8 N---H = 3,46 Å Megazol-N9 e TYR491-H7 N---H = 2,86 Å Megazol-N12 e TYR491-H7 N---H = 3,16 Å Megazol-N9 e FMN-H4 N---H = 3,90 Å Megazol-N12 e FMN-H4 N---H = 3,72 Å Megazol-H13 e FMN-O9 O---H = 1,89 Å Megazol-H13 e FMN-O9 O---H = 3,54 Å
Apêndice H - Distâncias das interações hidrofóbicas realizadas pelos derivados nitroimidazólicos (41a, 41e, 41f, 41d e 41h), benzonidazol, nifutimox, nitrofurazona e megazol nas simulações de docagem molecular.
Composto Interações Hidrofóbicas
Participantes Distância 41a 41a-C4 e FMN-C15 C---C = 4,68 Å 41a-C13 e FMN-C2 C---C = 3,45 Å 41a-C11 e FMN-C4 C---C = 4,55 Å 41a-C13 e ALA430-C6 C---C = 3,92 Å 41a-C13 e LEU431-C6 C---C = 3,74 Å 41a-C5 e TYR496-C7 C---C = 3,21 Å 41a-C5 e TRP235-C2 C---C = 4,18 Å 41a-C5 e LEU507-C7 C---C = 4,35 Å 41a-C5 e TYR545-C8 C---C = 3,83 Å 41a-C5 e LEU507-C8 C---C = 4,54 Å 41a-C4 e LEU507-C7 C---C = 3,63 Å 41a-C5 e TYR491-C7 C---C = 4,21 Å 41d 41d-C5 e TYR500-C1 C---C = 3,63 Å 41d-C6 e TYR500-C1 C---C = 3,26 Å 41d-C3 e TYR500-C1 C---C = 4,06 Å 41d-C11 e TYR545-C8 C---C = 4,47 Å 41d-C17 e TYR545-C8 C---C = 3,70 Å 41d-C16 e TYR545-C8 C---C = 4,41 Å 41d-C18 e TYR545-C8 C---C = 4,30 Å 41d-C5 e TYR496-C1 C---C = 3,91 Å
Apêndice H - Distâncias das interações hidrofóbicas realizadas pelos derivados nitroimidazólicos (41a, 41e, 41f, 41d e 41h), benzonidazol, nifutimox, nitrofurazona e megazol nas simulações de docagem molecular.
Composto Interações Hidrofóbicas
41d Participantes Distância 41d-C5 e LEU507-C7 C---C = 4,59 Å 41d-C11 e LEU507-C7 C---C = 3,67 Å 41d-C15 e LEU507-C7 C---C = 4,20 Å 41d-C4 e FMN-C2 C---C = 4,07 Å 41d-C5 e FMN-C2 C---C = 3,53 Å