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Previous issue date: 2016-08-04 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / In this work, semi and thiosemicarbazones selected from the LaDMol-QM library, were used
to study their interactions with a metalloproteinase from the snake Bothrops pauloensis
(BpMP-I) by molecular modelling and enzymatic inhibition assays with the toxin. The
crystalographic structure of BaPI (PDB code: 2W12) was used as a mold to build the 3D
model of BpMP-I by homology modeling. The theorical model of BpMP-I showed good
quality parameters and was used in a subsequent molecular modeling study. The
thiossemicarbazones showed better molecular docking results and in vitro enzymatic
inhibitions assays than semicarbazones. Studies by semi-empirical methods indicate a positive
enthalpy of interaction, suggesting that the enzyme inhibition by these compounds must be a
entropy-driven process. The results were used together to select the LDQM-IN-23 compound
and propose rationally designed modifications to improve the interactions with the toxin. The
study of the catalytic site of BpMP-I showed that there is an adjacent pocket with amino
groups of the peptide bonds available for interaction. All results were used together to design
structural changes, aiming the enhancing of the interaction with toxin. Therefore, was
proposed the insertion of the carboxyl group with different spacers, containing 2 (LDQM-IN-
23b) and 3 methylene groups (LDQM-IN-23c). The docking results and semi-empiric
optimization showed that there was a considerable improvement in the interaction for the
modified compounds. The modified compounds were synthesized and tested for biological
and enzymatic inhibition activity. It was observed that the IC50 values have improved: the
original molecule, LDQM-IN-23 has an IC50 of 3,011 ?M and the modified molecules have
IC50 of 79.12 (LDQM-IN-23b) and 1.77 ?M (LDQM-IN-23c). These molecules were tested
for inhibition of hemorrhagic activity induced by Bothropoidin, a P-III class
metalloproteinase, and by the B. pauloensis whole snake venom. The three molecules can
inhibit the hemorrhagic activity induced by isolated toxin and whole venom, and LDQM-IN-
23c showed higher efficiency compared with the other two, and in a rate of 1:10 (w/w
venom/inhibitor) the inhibition of the hemorrhagic activity was 100%. A molecular docking
study of this lead compound with Snake Venom Metalloproteases (SVMPs) from different
snake species and genera showed that this molecule can effectivelly interact with these
SVMPs. / Neste trabalho, foram utilizadas semi e tiossemicarbazonas, selecionadas na quimioteca do
LaDMol-QM (Dequim-UFRRJ), para o estudo das intera??es destas com o s?tio ativo de uma
metaloprotease da pe?onha da serpente Bothrops pauloensis por modelagem molecular e
ensaios de inibi??o da atividade enzim?tica e biol?gica sobre a toxina. A estrutura
cristalogr?fica de uma metaloprotease (BaPI) complexada com um inibidor (um
peptideomim?tico) (c?digo PDB 2W12) foi utilizada como molde para a constru??o do
modelo 3D da metaloprotease da pe?onha de B. pauloensis (BpMP-I). O modelo 3D te?rico
da BpMP-I, in?dito para esta toxina, apresentou bons par?metros de qualidade, sendo
considerado adequado para estudos de planejamento de ligantes baseado na estrutura. As
tiossemicarbazonas obtiveram melhores resultados, quando comparados com os resultados
das semicarbazonas, tanto para os ensaios de docagem molecular quanto para estudos de
inibi??o da atividade enzim?tica in vitro. Estudos por m?todos semiemp?ricos indicam uma
entalpia de intera??o positiva, sugerindo que a inibi??o enzim?tica por estes compostos deve
ser um processo controlado entropicamente. Os resultados foram utilizados para selecionar o
derivado LDQM-IN-23 e propor modifica??es estruturais planejadas racionalmente, visando
melhorar a intera??o deste com a toxina. O estudo do s?tio catal?tico da metaloprotease
mostrou que esta possui uma cavidade adjacente com grupos amino das liga??es pept?dicas
dispon?veis para intera??o. Foi proposta, ent?o, a inser??o de um grupo carboxilato com
diferentes espa?adores, 2 (LDQM-IN-23b) e 3 grupos metileno (LDQM-IN-23c). Os
resultados de docagem e otimiza??o semi-emp?rica mostraram que houve uma melhora
consider?vel na intera??o dos ligantes modificados, os quais foram sintetizados e testados
para as atividades de inibi??o enzim?tica e biol?gica. Na inibi??o enzim?tica, houve melhora
da CI50 com o aumento do espa?ador. O composto LDQM-IN-23 tem CI50 de 3011,00 ?M e
os compostos modificados possuem a CI50 de 79,12 (LDQM-IN-23b) e 1,77 ?M (LDQM-IN-
23c). Estes compostos foram testados para a inibi??o da atividade hemorr?gica in vivo
induzida pela Botropoidina, uma metaloprotease da classe P-III, e pela pe?onha bruta de B.
pauloensis. Os tr?s compostos conseguiram inibir a atividade hemorr?gica induzida pela
toxina isolada e pela pe?onha, sendo que o composto LDQM-IN-23c mostrou maior
efici?ncia, quando comparado com os outros dois, e para a propor??o de 1:10 (m/m
pe?onha/inibidor) a inibi??o da atividade foi de 100%. Foi realizado um estudo de docagem
deste composto l?der com outras metaloproteases de pe?onha de serpentes (SVMPs ? Snake
Venom Metalloproteinases), de esp?cies e g?neros diferentes, mostrando que este ligante
consegue interagir com outras SVMPs e ? um candidato para inibir a atividade hemorr?gica
de SVMPs presentes na pe?onha, n?o s? de B. pauloensis, mas de outras serpentes
| Identifer | oai:union.ndltd.org:IBICT/oai:localhost:jspui/1655 |
| Date | 04 August 2016 |
| Creators | Ferreira, Francis Barbosa |
| Contributors | Sant'Anna, Carlos Mauricio Rabello de, ?vila, Veridiana de Melo Rodrigues, Albuquerque, Magaly Gir?o, Rodrigues, Renata Santos, Castro, Rosane Nora, Pontes, Emerson Guedes |
| Publisher | Universidade Federal Rural do Rio de Janeiro, Programa de P?s-Gradua??o em Qu?mica, UFRRJ, Brasil, Instituto de Ci?ncias Exatas |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/doctoralThesis |
| Format | application/pdf |
| Source | reponame:Biblioteca Digital de Teses e Dissertações da UFRRJ, instname:Universidade Federal Rural do Rio de Janeiro, instacron:UFRRJ |
| Rights | info:eu-repo/semantics/openAccess |
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