Avaliação computacional de inibidores de fosfolipase a 2 de peçonha de bothrops brazili
Myotoxicity caused by snakebite envenoming emerges as one of the main problems of ophidic accidents as it is not well neutralized by the current serum therapy. A promising alternative is to search for efficient small molecule inhibitors that can act against multiple venom components. Phospholipas...
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| Formato: | doctoralThesis |
| Idioma: | pt_BR |
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Universidade Federal do Rio Grande do Norte
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| Endereço do item: | https://repositorio.ufrn.br/handle/123456789/56584 |
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| Resumo: | Myotoxicity caused by snakebite envenoming emerges as one of the main problems of
ophidic accidents as it is not well neutralized by the current serum therapy. A promising
alternative is to search for efficient small molecule inhibitors that can act against multiple
venom components. Phospholipase A2 (PLA2) is frequently found in snake venom and is
usually associated with myotoxicity. Thus it represents an excellent target for the search of
new treatments. Initially, the interaction of PLA2 with membrane models composed of 1-
palmitoyl-2-oleoyl phosphatidylglycerol (POPG) and 1-palmitoyl-2-oleoyl
phosphatidylcholine (POPC) was designed to identify the most important protein residues for
interaction with the membrane. Subsequently, the effect of temperature on the inhibition of
the catalytic properties of PLA2 from Bothrops brazili venom by rosmarinic (RSM) and
chlorogenic (CHL) acids was analyzed through experimental and computational approaches.
Three temperatures were evaluated (25, 37 and 50°C). In the experimental section, enzymatic
assays showed that RSM is a better inhibitor in all three temperatures. At 50°C, the inhibition
efficiency decayed significantly for both acids. Docking studies revealed that both ligands
bind to the hydrophobic channel of the protein dimer where the phospholipid binds in the
catalytic process, interacting with several functional residues. In this context, RSM presents
better interaction energies due to stronger interactions with chain B of the dimer. Molecular
dynamics simulations showed that RSM can establish selective interactions with ARG112B of
PLA2, which is located next to residues of the putative Membrane Disruption Site in PLA2-
like structures. The affinity of RSM and CHL acids towards PLA2 is mainly driven by
electrostatic interactions, especially salt bridge interactions established with residues
ARG33B (for CHL) and ARG112B (RSM) and hydrogen bonds with residue ASP89A. The
inability of CHL to establish a stable interaction with ARG112B was pointed as the reason for
its lower inhibition efficiency. The lower protein conformational stability promoted by ligands
at 37°C for CHL and at 50°C for RSM was indicated as the reason for the lower inhibition
efficiency at these respective temperatures. |
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