Banca de QUALIFICAÇÃO: EDUARDO AUGUSTO DA SILVA DINIZ

Uma banca de QUALIFICAÇÃO de DOUTORADO foi cadastrada pelo programa.
STUDENT : EDUARDO AUGUSTO DA SILVA DINIZ
DATE: 27/04/2023
TIME: 09:00
LOCAL: videoconferência
TITLE:

COMPUTATIONAL EVALUATION OF PHOSPHOLIPASE A₂ INHIBITORS FROM Bothrops Brazili VENOM

KEY WORDS:

Molecular dynamics; Phospholipase A2; Enzymatic inhibition

PAGES: 90
BIG AREA: Ciências Exatas e da Terra
AREA: Química
SUBÁREA: Físico-Química
SPECIALTY: Química Teórica
SUMMARY:

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.

COMMITTEE MEMBERS:
Presidente - 1959889 - DAVI SERRADELLA VIEIRA
Externo ao Programa - 1893445 - EUZEBIO GUIMARAES BARBOSA - nullExterno ao Programa - 095.586.284-17 - SERGIO RUSCHI BERGAMACHI SILVA